Quinuclidine derivatives and pharmaceutical compositions containing the same

ABSTRACT

Carbamates of formula (I) or pharmaceutically acceptable salts thereof, including quaternary ammonium salts of formula (II) are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as antagonists of M3 muscarinic receptors.

This invention relates to new therapeutically useful quinuclidinecarbamate derivatives, to some processes for their preparation and topharmaceutical compositions containing them.

The structures according to the invention are antimuscarinic agents witha potent and long lasting effect. In particular, these compounds showhigh affinity and selectivity for muscarinic M3 receptors over M2receptors. The M3 subtype of muscarinic receptor is present in glandsand smooth muscle and mediates the excitatory effects of theparasympathetic system on glandular secretion and on the contraction ofvisceral smooth muscle (Chapter 6, Cholinergic Transmission, in H. P.Rang et al., Pharmacology, Churchill Livingstone, New York, 1995).

M3 antagonists are therefore known to be useful for treating diseasescharacterised by an increased parasympathetic tone, by excessiveglandular secretion or by smooth muscle contraction (R. M. Eglen and S.S. Hegde, (1997), Drug News Perspect., 10(8):462-469).

Examples of this kind of diseases are respiratory disorders such aschronic obstructive pulmonary disease (COPD), bronchitis, bronchialhyperreactivity, asthma, cough and rhinitis; urological disorders suchas urinary incontinence, pollakiuria, neurogenic or unstable bladder,cystospasm and chronic cystitis; gastrointestinal disorders such asirritable bowel syndrome, spastic colitis, diverticulitis and pepticulceration; and cardiovascular disorders such as vagally induced sinusbradycardia (Chapter 7, Muscarinic Receptor Agonists and Antagonists, inGoodman and Gilman's The Pharmacological Basis of Therapeutics, 10theedition, McGraw Hill, Ney York, 2001.).

The compounds of the invention can be used alone or in association withother drugs commonly regarded as effective in the treatment of thesediseases. For example, they can be administered in combination withβ₂-agonists, steroids, antiallergic drugs, phosphodiesterase IVinhibitors and/or leukotriene D4 (LTD4) antagonists for simultaneous,separate or sequential use in the treatment of a respiratory disease.

The present invention provides new quinuclidine carbamate derivativeswith potent antagonist activity at muscarinic M3 receptors, which fallunder the chemical structure described in formula (I) or arepharmaceutically acceptable salts thereof, including quaternary salts offormula (II).

Formula (I) represents a carbamate of the following general structure:

wherein

R1 represents a group selected from phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl,thiophen-2-ylmethyl, and thiophen-3-ylmethyl;

R2 represents a group selected from optionally substituted lower alkyl,optionally substituted lower alkenyl, optionally substituted loweralkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturatedcycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl,furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, andpyridylmethyl; wherein the carbocyclic moieties in the cycloalkyl,cycloalkylmethyl, phenyl, benzyl or phenethyl groups can be optionallybridged or fused to another saturated, unsaturated or aromaticcarbocyclic moiety or to a cyclic moiety comprising carbon atoms and 1or 2 oxygen atoms;

the cyclic groups present in R1 and R2 being optionally substituted byone, two or three substituents selected from halogen, straight orbranched, optionally substituted lower alkyl, hydroxy, straight orbranched, optionally substituted lower alkoxy, —SH, straight or branchedoptionally substituted lower alkylthio, nitro, cyano, —NR′R″, —CO₂R′,—C(O)—NR′R″, —N(R′″)C(O)—R′, —N(R′″)—C(O)NR′R″, wherein R′, R″ and R′″each independently represents a hydrogen atom or a straight or branched,optionally substituted lower alkyl group or R′ and R″ together with theatom to which they are attached form a cyclic group;

p is 1 or 2 and the carbamate group is attached at positions 2, 3 or 4of the azabicyclic ring,

and pharmaceutically acceptable salts thereof, including quaternaryammonium salts of formula (II)

wherein R1, R2 and p are as defined above;

m is an integer from 0 to 8;

n is an integer from 0 to 4;

A represents a group selected from —CH₂—, —CH═CR′—, —CR═CH—, —CR′R″—,—C(O)—, —O—, —S—, —S(O)—, —S(O)₂— and —NR′—, wherein R′ and R″ are asdefined above;

B represents a hydrogen atom, or a group selected from straight orbranched, optionally substituted lower alkyl, hydroxy, straight orbranched, optionally substituted lower alkoxy, cyano, nitro, —CH═CR′R″,—C(O)OR′, —OC(O)R′, —SC(O)R′, —P(O)NR′R″, —NR′C(O)OR″, —NR′C(O)NR″,cycloalkyl, phenyl, naphthanelyl, 5,6,7,8-tetrahydronaphthanelyl,benzo[1,3]dioxolyl, heteroaryl or heterocyclyl; R′ and R″ being asdefined above; and wherein the cyclic groups represented by B areoptionally substituted by one, two or three substitutuents selected fromhalogen, hydroxy, straight or branched, optionally substituted loweralkyl, phenyl, —OR′, —SR′, —NR′R″, —NHCOR′, —CONR′R″, —CN, —NO₂ and—COOR′; R′ and R″ being as defined above;

X⁻ represents a pharmaceutically acceptable anion of a mono orpolyvalent acid;

including all individual stereoisomers of formulae (I) or (II) andmixtures thereof;

with the proviso that the compound of formula (I) is not one of

Diphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-yl ester

Ethylphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-yl ester

Further objectives of the present invention are to provide processes forpreparing said compounds; pharmaceutical compositions comprising aneffective amount of said compounds; the use of the compounds in themanufacture of a medicament for the treatment of diseases susceptible ofbeing improved by antagonism of M3 muscarinic receptors; and methods oftreatment of diseases susceptible to amelioration by antagonism of M3muscarinic receptors, which methods comprise the administration of thecompounds of the invention to a subject in need of treatment.

In the compounds of the invention it is preferred that at least one ofR1 or R2 be substituted. Particularly preferred compounds of formula (I)or (II) are those wherein when the cyclic group present in R1 isunsubstituted or has only one substitutent R2 has at least onesubstituent. Also preferred are compounds wherein when R2 is notsubstituted the cyclic group present in R1 has at least twosubstituents.

J. L. G. Nilsson et al. describe in Acta Pharm. Suecica, 5:71-76 (1968)a group of quinuclidine carbamate derivatives having antimalarialactivity, among which diphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-ylester and ethylphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-yl ester arementioned.

WO 02/00652 discloses a group of compounds which fall under the generalstructure of formula (I) or (II). The specific compounds disclosed inthat application are excluded from the present invention.

Thus, in those compounds of formula (I) as described above, wherein

p is 2;

the carbamate group is attached at position 3 of the azabicyclic ring;

and R1 is an unsubstituted indanyl group or a phenyl group, which isoptionally substituted with one or two substitutents selected fromchlorine, fluorine, bromine, methyl, hydroxy and cyano;

then R2 cannot be one of: unsubstituted cyclopropylmethyl; unsubstitutedcyclobutylmethyl; unsubstituted cyclopentylmethyl; cyclohexylmethyloptionally substituted with a methyl or an isopropenyl group;unsubstituted cyclohexenyl; unsubstituted norbornenyl; unsubstitutedbicyclo[2,2,1]heptanyl; unsubstituted benzo[1,3]dioxolyl; unsubstituted2,3-dihydrobenzo[1,4]dioxinyl; unsubstituted benzyl; a benzyl groupwhich is substituted with one or two substituents selected fromfluorine, chlorine, bromine, methoxy, methyl, trifluoromethyl, ethyl,tertbutyl, hydroxy, hydroxymethyl, cyano, aminocarbonyl,trifluoromethoxy, benzyloxy, isopropyloxy; and a benzyl group which issubstituted with three fluorine atoms.

Further, in those compounds of formula (II) as described above wherein

p is 2;

the carbamate group is attached at position 3 of the azoniabicyclic ringhaving (3R)-configuration;

R1 is a phenyl group which is optionally substituted with a fluorineatom or a methyl group;

R2 is an unsubstituted cyclohexylmethyl group or a benzyl group which isoptionally substituted with one or three fluorine atoms;

and X— iodine;

then, the sequence B—(CH₂)_(n)-A-(CH₂)_(m)— cannot be a methyl group.

More specifically, the following compounds are explicitly excluded fromthe scope of the invention:(3R)-3-(Benzylphenylcarbamoyloxy)-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide(3R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide(3R)-3-(Benzyl-o-tolylcarbamoyloxy)-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide(3R)-1-Methyl-3-[o-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]1-azoniabicyclo[2.2.2]octaneiodide(3R)-3-[(4-Fluorobenzyl)-m-tolylcarbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide(3R)-3-[Benzyl-(2-fluorophenyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide(3R)-3[-Cyclohexylmethyl-(2-fluorophenyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide

As used herein, an alkyl, alkenyl or alkynyl group or moiety can bestraight or branched, and is typically a lower alkyl, alkenyl or alkynylgroup. A lower alkyl group contains 1 to 8, preferably 1 to 6, carbonatoms. Examples include methyl, ethyl, propyl, including i-propyl,butyl, including n-butyl, sec-butyl and tert-butyl, 1-methylbutyl,1-ethylpropyl, 1,2-dimethylpropyl, n-hexyl or 1-ethylbutyl groups. Morepreferably a lower alkyl group contains from 1 to 4 carbon atoms. Alower alkenyl or alkynyl group contains 2 to 8, preferably 2 to 6,carbon atoms. Examples include vinyl, allyl, 1-propenyl, 4-pentenyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl groups. Morepreferably, a lower alkenyl or alkynyl group contains 2 to 4 carbonatoms.

Optionally substituted lower alkyl, alkenyl or alkynyl groups mentionedherein include straight or branched lower alkyl, alkenyl or alkynylgroups as defined above, which may be unsubstituted or substituted inany position by one or more substituents, for example by 1, 2 or 3substituents. When two or more substituents are present, eachsubstituent may be the same or different. The substituent(s) aretypically halogen atoms, preferably fluoride atoms, and hydroxy oralkoxy groups.

Alkoxy and alkylthio groups mentioned herein are typically lower alkoxyand alkylthio groups, that is groups containing from 1 to 8, preferably1 to 6 and more preferably 1 to 4 carbon atoms, the hydrocarbon chainbeing branched or straight and optionally substituted in any position byone or more substituents, for example by 1; 2 or 3 substituents. Whentwo or more substituents are present, each substituent may be the sameor different. The substituent(s) are typically halogen atoms, mostpreferably fluoride atoms, and hydroxy groups. Preferred optionallysubstituted alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, sec-butoxy, t-butoxy, trifluoromethoxy, difluoromethoxy,hydroxymethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy. Preferredoptionally substituted alkylthio groups include methylthio, ethylthio,n-propylthio, i-propylthio, n-butylthio, sec-butylthio, t-butylthio,trifluoromethylthio, difluoromethylthio, hydroxymethylthio,2-hydroxyethylthio or 2-hydroxypropylthio.

Cyclic groups mentioned herein include, unless otherwise specified,carbocyclic and heterocyclic groups. The cyclic groups can contain oneor more rings. Carbocyclic groups may be aromatic or alicyclic, forexample cycloalkyl groups. Heterocyclic groups also include heteroarylgroups.

Cycloalkyl groups and alicyclic groups mentioned herein, unlessotherwise specified, typically contain from 3 to 7 carbon atoms.Cycloalkyl groups and alicyclic rings of 3 to 7 carbon atoms includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein an aromatic group typically contains from 5 to 14,preferably 5 to 10 carbon atoms. Examples of aromatic groups includephenyl and naphthalenyl.

A heterocyclic or heteroaromatic group mentioned herein is typically a 5to 10 membered group, such as a 5, 6 or 7 membered group, containing oneor more heteroatoms selected from N, S and O. Typically, 1, 2, 3 or 4heteroatoms are present, preferably 1 or 2 heteroatoms. A heterocyclicor heteroaromatic group may be a single ring or two or more fused ringswherein at least one ring contains a heteroatom. Examples ofheterocyclic groups include piperidyl, pyrrolidyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, imidazolidinyl,pyrazolinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, quinuclidinyl,triazolyl, pyrazolyl, tetrazolyl and thienyl. Examples of heteroaromaticgroups include pyridyl, thienyl, furyl, pyrrolyl, imidazolyl,benzothiazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,triazolyl and-pyrazolyl.

As used herein a halogen atom includes a fluorine, chlorine, bromine oriodine atom, typically a fluorine, chlorine or bromine atom.

As used herein, the term pharmaceutically acceptable salt embraces saltswith a pharmaceutically acceptable acid or base. Pharmaceuticallyacceptable acids include both inorganic acids, for example hydrochloric,sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitricacid and organic acids, for example citric, fumaric, maleic, malic,formic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic,methanesulphonic, ethanesulphonic, benzenesulphonic orp-toluenesulphonic acid.

In the quaternary ammonium compounds of the present invention, includingthose represented by formula (II), an equivalent of an anion (X⁻) isassociated with the positive charge of the N atom. X⁻ may be an anion ofvarious mineral acids such as, for example, chloride, bromide, iodide,sulphate, nitrate, phosphate, or an anion of an organic acid such as,for example, acetate, trifluoroacetate, maleate, fumarate, citrate,oxalate, succinate, tartrate, malate, mandelate, formate,methanesulfonate and p-toluenesulfonate. X⁻ is preferably an anionselected from chloride, bromide, iodide, sulphate, nitrate, acetate,trifluoroacetate, formate, methanesulfonate, maleate, oxalate orsuccinate. More preferably X⁻ is chloride, bromide, formate,trifluoroacetate or methanesulfonate.

Preferred compounds of formula (I) according to the invention as definedabove are those wherein R1 represents a group selected from 2-furyl,3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl,furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; the cyclicgroups present in R1 being optionally substituted by one, two or threesubstituents selected from halogen, straight or branched, optionallysubstituted lower alkyl, hydroxy, straight or branched, optionallysubstituted lower alkoxy, —SH, straight or branched optionallysubstituted lower alkylthio, nitro, cyano, —NR′R″, —CO₂R′, —C(O)—NR′R″,—N(R′″)C(O)—R′, —N(R′″)—C(O)NR′R″, wherein R′, R″ and R′″ eachindependently represents a hydrogen atom or a straight or branched,optionally substituted lower alkyl group or R′ and R″ together with theatom to which they are attached form a cyclic group;

Also preferred are compounds of formula (I) as defined above wherein R2represents an optionally substituted group selected from lower alkyl,lower alkenyl, lower alkynyl, saturated or unsaturated cycloalkyl,phenyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl,thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, and pyridylmethyl ora saturated or unsaturated cycloalkylmethyl group which has at least onesubstituent and is selected from substituted cyclopropylmethyl,substituted cyclobutylmethyl and substituted cyclopentylmethyl; thesubstituents of the cyclic groups present in R2 being one, two or threesubstituents selected from halogen, straight or branched, optionallysubstituted lower alkyl, hydroxy, straight or branched, optionallysubstituted lower alkoxy, —SH, straight or branched optionallysubstituted lower alkylthio, nitro, cyano, —NR′R″, —CO₂R′, —C(O)NR′R″,—N(R′″)C(O)—R′, —N(R′″)(O)NR′R″, wherein R′, R″ and R′″ eachindependently represents a hydrogen atom or a straight or branched,optionally substituted lower alkyl group or R′ and R″ together with theatom to which they are attached form a cyclic group;

Preferred compounds of formula (II) according to the invention asdefined above are those wherein R1 represents a group selected fromphenyl, 2-thienyl, 3-thienyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl,furan-2-ylmethyl or furan-3-ylmethyl, the cyclic groups present in R1being optionally substituted with one to three substitutents selectedfrom fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl,ethyl, tert-butyl, hydroxy and cyano.

In particularly preferred embodiments R1 represents a group selectedfrom phenyl, 2-fluorophenyl, 3-flurorophenyl, 4-fluorophenyl,3-methylphenyl, 4-methylphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,2,4,5-trifluorophenyl, 5-methylfuran-2-ylmethyl,4-fluoro-2-methylphenyl, 3-fluoro-4-methoxyphenyl,3-methyl-thiophen-2-ylmethyl, 4,5-dimethyl-thiophen-2-ylmethyl,thiophen-3-ylmethyl, 5-methyl-furan-2-ylmethyl,5-methyl-2-trifluoromethyl-furan-3-ylmethyl, and2,5-dimethyl-furan-3-ylmethyl,

Also preferred are compounds of formula (II) as defined above wherein R2represents a pent-4-enyl, pentyl, butyl, allyl, benzyl,thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl,furan-3-ylmethyl, phenethyl, cyclopentyl, cyclohexyl or cyclohexylmethylgroup, the cyclic groups present in R2 being optionally substituted withone to three substitutents selected from fluorine, chlorine, bromine,methyl, methoxy, trifluoromethyl, ethyl, tert-butyl, hydroxy and cyano.

In particularly preferred embodiments R2 represents a group selectedfrom 3-fluorobenzyl, 2,4,5-trifluorobenzyl, 3,4,5-trifluorobenzyl,5-Bromothiophen-2-ylmethyl, 3,4-dimethoxyphenylethyl,3-methylthiophen-2-ylmethyl, thiophen-3-ylmethyl,4-bromo-5-methylthiophen-2-ylmethyl, 4,5-dimethylfuran-2-ylmethyl,furan-3-ylmethyl, 2-fluoro-4-methoxybenzyl, 2-(4-fluorophenyl)ethyl,butyl, pent-4-enyl and cyclopentyl.

Further preferred compounds of formula (II) are those wherein A is—CH2-, m and n are both 0, and B represents a group selected fromstraight or branched, optionally substituted lower alkyl, hydroxy,straight or branched, optionally substituted lower alkoxy, cyano, nitro,—CH═CR′R″, —C(O)OR′, —OC(O)R′, —SC(O)R′, —C(O)NR′R″, —NR′C(O)OR″,—NR′C(O)NR″, cycloalkyl, phenyl, riaphthanelyl,5,6,7,8-tetrahydronaphthanelyl, benzo[1,3]dioxolyl, heteroaryl orheterocyclyl; R′ and R″ being as defined above; and wherein the cyclicgroups represented by B are optionally substituted by one, two or threesubstitutuents selected from halogen, hydroxy, straight or branched,optionally substituted lower alkyl, phenyl, —OR′, —R′, —NR′R″, —NHCOR′,—CONR′R″, —CN, —NO2 and —COOR′; R′ and R″ being as defined above;

In other embodiments of formula (II) A is —CH2-, B is as defined aboveand at least one of m or n is not 0.

Also preferred are compounds of formula (II) wherein B represents athiophen-2-yl group or a phenyl group which is optionally substitutedwith one to three substituents selected from halogen atoms, or hydroxy,methyl, —CH2OH, —OMe, —NMe2, —NHCOMe, —CONH2, —CN, —NO2, —COOMe, or —CF3groups. Most preferred are compounds wherein B represents a phenyl,4-fluorophenyl, 3-hydroxyphenyl or thiophen-2-yl group.

In particularly preferred compounds of formula (II) n=0 or 1; m is aninteger from 1 to 6; and A represents a —CH2-, —CH═CH—, —CO, —NMe, —O—or —S— group. Most preferred are compounds wherein m is 1, 2 or 3 and Arepresents a —CH2-, —CH═CH—, or —O— group.

Preferably, in compounds of formula (II) the sequenceB—CH₂)_(n)-A-(CH₂)_(m)— represents a group selected from3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl,3-thiophen-2-ylpropyl, allyl, heptyl, 3-cyanopropyl and methyl.

X— represents in the preferred embodiments of formula (II) a chloride,bromide, trifluoroacetate or methanesulphonate anion.

Also preferred are compounds of formula (I) or (II) wherein p is 2and/or wherein the azabicyclic ring is substituted in the 3-position.

The compounds of the present invention represented by formula (I) andsalts thereof such as those represented by formula (II), may have one ormore asymmetric carbons. All possible stereoisomers are included, suchas compounds of formula (I) or (II) wherein the carbon at the 3-positionof the azabicyclic ring has either R or S configuration. All singleisomers and mixtures of the isomers fall within the scope of the presentinvention.

The following compounds of general formula (I) are intended toillustrate the general scope of the present invention.(3-Fluorobenzyl)-(3-fluorophenyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterm-Tolyl-2,4,5-trifluorobenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterCyclohexylmethyl-(2-fluorophenyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3yl ester[2-(3,4-Dimethoxyphenyl)ethyl]-(5methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3yl ester(5-Bromothiophen-2-ylmethyl)-(2,4,5-trifluorophenyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterThiophen-3-ylmethyl-(2,4,5-trifluorobenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(4-Bromo-5-methylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamicacid (3R)-1-azabicyclo[2.2.2]oct-37-yl ester(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterFuran-3-ylmethyl-(5methyl-2-trifluoromethylfuran-3-ylmethyl)carbamicacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester(2,6-Difluorophenyl)pent-4-enylcarbamic acid(3R)-1-aza-bicyclo[2.2.2]oct-3-yl ester(2,5-Dimethylfuran-3-ylmethyl)-(2-fluoro-4-methoxybenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester[2-(4-Fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3yl ester Butyl-(2,5-difluorophenyl)carbamicacid (3R)-1-azabicyclo[2.2.2]oct-3yl esterCyclopentyl-(4,5dimethylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester Benzylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Benzyl(4-fluorophenyl)carbamic acid1-azabicyclo[2.2.2]oct-(R)yl ester Benzyl-p-tolylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Butylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Phenylthiophen-2-ylmethylcarbamicacid 1-azabicyclo[2.2.2]oct-3-(R)yl ester Phenethylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Pentylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Pent-4-enylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Phenylthiophen-3-ylmethylcarbamicacid 1-azabicyclo[2.2.2]oct-3-(R)yl esterButylthiophen-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)ylester Bis-thiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl esterFuran-2-ylmethyl-2-thiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Allylthiophen-2-ylmethylcarbamicacid 1-azabicyclo[2.2.2]oct-3-(R)yl esterCyclopentylthiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Furan-2-ylmethylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Bis-furan-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester Benzylphenylcarbamic acid1-azabicyclo[2.2.1]hept-4-yl ester Benzylphenylcarbamic acid1-azabicyclo[2.2.2]oct-4-yl ester(5-Ethylthiophen-2-ylmethyl)-(3methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterCyclopentyl-(5ethylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester and pharmaceutically acceptablesalts thereof.

The following salts of general formula (II) are intended to illustratethe general scope of the present invention.(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-(2-Phenoxyethyl)-3-[m-tolyl-(2,4,5trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-(3-Phenylpropyl)-3-[m-tolyl-2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[Cyclohexylmethyl-(2-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[Cyclohexylmethyl-(2-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-Allyl-3-[[2(3,4dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(5-Bromothiophen-2-y-methyl)(2,4,5-trifluorophenyl)carbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[[2-3,4-dimethoxyphenyl)ethyl-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octaneformate(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-Phenethyl-3-[thiophen-3-ylmethyl-(2,4,5-trifluorobenzyl)carbamoyloxy-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(4-Bromo5-methylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(4,5-Dimethylfuran-2-ylmethyl)-5-methylfuran-2-ylmethyl)carbamoyloxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-[3-(4-Fluorophenoxy)propyl]-3-[furan-3-ylmethyl-(5-methyl-2-trifluoromethylfuran-3-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2,5-Dimethylfuran-3-ylmethyl)-2-fluoro-4-methoxybenzyl)carbamoyloxy]-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[Butyl-(2,5-difluorophenyl)carbamoyloxy]-1-heptyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-(3-cyanopropyl)-3-[(2,6-difluorophenyl)pent-4-enylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[Cyclopentyl-(4,5-dimethylthiophen-2-ylmethyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate3-(R)(Benzylphenylcarbamoyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide1-Allyl-3-(R)(benzylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Benzylphenylcarbamoyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Benzylphenylcarbamoyloxy)-1-(3-thiophen-2-yl-propyl)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Benzylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Benzylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Butylphenylcarbamoyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide1-Allyl-3-(R)(butylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Butylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Butylphenylcarbamoyloxy)-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Butylphenylcarbamoyloxy)-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Butylphenylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Butylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Phenylthiophen-2-ylmethylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide1-(2-Phenoxy-ethyl)-3-R)-(phenyl-thiophen-2-ylmethyl-carbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide1-Allyl-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Phenethylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate1-Heptyl-3-(R)(pent-4-enylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate1-Allyl-3-R-(phenyl-thiophen-3-ylmethyl-carbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide1-(2-Phenoxyethyl)-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Bis-thiophen-2-ylmethylcarbamoyloxy)-1-3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide3-(R)(Bis-thiophen-2-ylmethylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide1-Allyl-3-(R)(allylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate3-(R)(Cyclopentylthiophen-2-ylmethylcarbamoyloxy-1-3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate3-(R)(Furan-2-ylmethylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate1-Allyl-3-(R)(bis-furan-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate(3R)-3-[(3-Fluorophenyl)-3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(5-Ethylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[Cyclopentyl-(5-ethylthiophen-2-ylmethyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octanebromide

Particularly preferred individual compounds of formula (I) include:[2-(3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethylcarbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(5-Bromothiophen-2-ylmethyl)-2,4,5-trifluorophenyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamic acid(3R)1-azabicyclo[2.2.2]oct-3-yl esterThiophen-3-ylmethyl(2,4,5-trifluorobenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(4-Bromo-5-methylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamicacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterFuran-3-ylmethyl-(5methyl-2-trifluoromethylfuran-3-ylmethyl)carbamicacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester(2,5-dimethylfuran-3-ylmethyl)-(2-fluoro-4-methoxybenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester[2-(4-Fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterButyl-(2,5-difluorophenyl)carbamic acid (3R)-1-azabicyclo[2.2.2]oct-3-ylester (2,6-Difluorophenyl)pent-4-enylcarbamic acid(3R)-1-aza-bicyclo[2.2.2]oct-3yl esterCyclopentyl-(4,5-dimethylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester(5-Ethylthiophen-2-ylmethyl)-3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3yl ester

Particularly preferred individual compounds of formula (II) include:(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-(2-Phenoxyethyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-(3Phenylpropyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-Allyl-3-[[2-(3,4-dimethoxyphenyl)ethyl)-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(5-Bromothiophen-2-ylmethyl)-2,4,5-trifluorophenyl)carbamoyloxy]1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[[2-(3,4-dimethoxyphenyl)ethyl-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-Phenethyl-3-[thiophen-3-ylmethyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(4-Bromo-5-methylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-[3-4-Fluorophenoxy)propyl]-3-[furan-3-ylmethyl-(5-methyl-2-trifluoromethylfuran-3-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2,5-Dimethylfuran-3-ylmethyl)-(2-fluoro-4-methoxybenzyl)carbamoyloxy]-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[Butyl-(2,5-difluorophenyl)carbamoyloxy]-1-heptyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-1-(3-cyanopropyl)-3-[(2,6-difluorophenyl)pent-4-enylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[Cyclopentyl-(4,5-dimethylthiophen-2-ylmethyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(5-Ethylthiophen-2-ylmethyl)(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethylcarbamoyloxy]-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octaneformate(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-1-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide

The present invention also provides processes for preparing compounds offormulas (I) and (II).

Compounds of general formula (I) may be prepared by method (a)illustrated in the following scheme and detailed in the experimentalsection.

In formulas (I), (III) and (IV), R1, R2 and p are as defined above.

Compounds of general formula (III) may be prepared from thecorresponding secondary amines following the standard method (b)described in literature.

Amines of general formula (V) that are not commercially available may beprepared by synthesis according to standard methods, such as alkylationof anilines or reductive alkylation. For example, amines wherein R1 is asubstituted thiophen-2-ylmethyl or a substituted furan-2-ylmethyl and R2is as defined above, may be obtained by reductive alkylation. Thecorresponding aldehyde is treated with the corresponding primary amineto form the imine, which is reduced with sodium borohydride in MeOH toobtain the secondary amine.

The carbamates of formula (I) may be converted to pharmaceuticallyacceptable salts by methods known in the art. Typically, a carbamate offormula (I) is treated with an inorganic or organic acid such asfumaric, tartaric, formic, succinic or hydrochloric acid.

The quaternary ammonium derivatives of general formula (II), may beprepared by reaction of an alkylating agent of general formula (VI) withcompounds of general formula (I), as described in the following scheme.In formulas (I), (II) and (V(I), R1, R2, A, B, X, n, m and p are asdefined above.

In formula (VI), W represents any suitable leaving group, such as agroup X as defined above. Preferably, W represents a group X.

This alkylation reaction may be carried out by two differentexperimental procedures, (c) and (d) which are described in theexperimental section below. In particular method (d) provides a newexperimental process, using solid phase extraction methodologies thatallow the parallel preparation of several compounds. If W represents agroup other than X, the quaternary ammonium salt of formula (II) isproduced from the product of method (c) or (d) by carrying out anexchange reaction according to standard methods to replace the anionwith the desired anion X.

Methods (c) and (d) are described in the experimental section. Compoundsof general formula (VI) which are not commercially available have beenprepared by synthesis according to standard methods. For example,compounds wherein n=0 and A=-O—, —S— or —NR4, wherein R4 is as definedabove, were obtained by reaction of the corresponding alcohol, thiol oramine derivative or its sodium or potassium salt with an alkylatingagent of general formula Y—(CH₂)_(m)—W, wherein W may be a halogen and Ymay be a halogen or a sulphonate ester. In other examples, compounds ofgeneral formula (V), where n>=1 were synthesised from the correspondingalcohol derivative of general formula (VII) by known methods.B—(CH₂)_(n)-A-(CH₂)_(m)—OH   (VII)

Compounds of formula (IV) could be:4-hydroxy-1-azabicyclo[2.2.1]heptane, described in WO93/150804-hydroxy-1-azabicyclo[2.2.2]octane, described in Grob, C. A. et. al.Helv. Chim. Acta (1958), 41, 1184-1190(3R)-3-hydroxy-1-azabicyclo[2.2.2]octane or(3S)-3-hydroxy-1-azabicyclo[2.2.2]octane, described in Ringdahl, R. ActaPharm Suec. (1979), 16, 281-283 and commercially available from CUChemie Uetikon GmbH.

The structures of the prepared compounds were confirmed by ¹H-NMR andMS. The NMR were recorded using a Varian 300 MHz instrument and chemicalshifts are expressed as parts per million (δ) from the internalreference tetramethyl silane. Their purity was determined by HPLC, usingreverse phase chromatography on a Waters instrument. Molecular ions wereobtained by electrospray ionization mass spectrometry on a HewlettPackard instrument. HPLC-MS experiments were performed on a Gilsoninstrument equipped with a binary pump (Gilson piston pump 321); avacuum degasser (Gilson 864); an injector-fraction collector (Gilsonliquid handler 215); two injection modules, analytical and preparative(Gilson 819); a valve (Gilson Valvemate 7000); a 1/1000 splitter(Acurate by LC Packings); a make-up pump (Gilson 307); a diode arraydetector (Gilson 170) and a MS detector (a Thermoquest Finnigan aQa, aquadrupole mass spectrometer with ES an APCI ionisation modes). TheHPLC-MS instrument was controlled by an IBM PC.

Method (a)

EXAMPLE 1 Preparation of butylphenylcarbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

0.65 g (28.50 mmol) of sodium was added to 70 ml of dry toluene. Thesuspension was refluxed with vigorous stirring. When all the sodium wasmelted, 3.60 g (28.30 mmol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octanewas added and stirring continued for 2 hours, by which time all thesodium had reacted to form the alcoholate. 6.00 g (28.30 mmol) ofPhenylbutylcarbamoyl chloride (Intermediate I-1) dissolved in 30 ml oftoluene was then slowly added. The mixture was refluxed for one hour,and then the reaction was stirred overnight at room temperature. Thesuspension was filtered and the filtrate evaporated. Ether was added tothe residue and stirred for 10 min. The suspension was filtered and thefiltrate concentrated in vacuo to obtain 7.18 g of brown oil. Thisproduct was purified by column chromatography (silica gel,chloroform/ethanol/ammonia 140:8:1) to yield 1.78 g (5.89 mmol) (22%) ofa pure product, structure confirmed by ¹H-NMR. ¹H-NMR (300 MHz,CDCl3): δ0.9 (m, 3H), 1.3 (m, 4H), 1.5 (m, 4H), 1.9 (s, 1H), 2.7 (m, 5H), 3.2 (m,1H), 3.7 (m, 2H), 4.7 (m, 1H), 7.2-7.4 (m, 5H); MS [M+1]⁺: 303.

EXAMPLE 2 Preparation of cyclopentylthiophen-2-ylmethylcarbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

0.57 g (24.59 mmol) of sodium was added to 70 ml of dry toluene. Thesuspension was refluxed with vigorous stirring. When all the sodium wasmelted, 3.11 g (24.42 mmol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octanewas added and stirred for 2 hours, by which time all the sodium hadreacted to form the alcoholate. 4.96 g (20.35 mmol) ofcyclopentylthiophen-2-ylmethylcarbamoyl chloride (Intermediate 1-2)dissolved in 30 ml of toluene was then slowly added. The mixture wasrefluxed for five hours, and then the reaction was stirred overnight atroom temperature. The suspension was filtered and the filtrate washedwith water. The organic layer was extracted with 20 % HCl and theaqueous layer basified with 8N NaOH and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous Na₂SO₄ andevaporated. The oil obtained (4.50 g) was purified by columnchromatography (silica gel, chloroform/ethanol/ammonia 225:8:1) toobtain 2.25 g (6.73 mmol) (33%) of a pure product, structure confirmedby ¹H-NMR.

1H-NMR (300 MHz, DMSO-d₆): δ 1.20-1.40 (m, 1H), 1.45-1.72 (m, 11H), 1.89(bs, 1H), 2.45-2.62 (m, 5H), 3.03-3.10 (m, 1H), 4.22 (bs, 1H), 4.50-4.63(m, 3H), 6.93-6.99 (m, 2H), 7.38 (m, 1H).; MS [M+1]⁺: 335.

EXAMPLE 3 Preparation of Benzylphenylcarbamic acid1-azabicyclo[2.2.1]hept-4-yl ester

In a two necked flask under nitrogen, 3 ml of THF and 150 mg (1.33mmoles) of 4-hydroxy-1-azabicyclo[2.2.1]heptane were placed. Thesuspension was cooled to −60° C. and 0.7 ml (1.46 mmoles) of LDA wasadded dropwise. After the addition the temperature was allowed to riseto 0° C. and was kept during two hours. A solution of 295 mg (1.20mmoles) of benzylphenylcarbamoyl chloride in 2 ml of THF was added in 30minutes. The reaction mixture was allowed to slowly warm to roomtemperature and stirred for 18 hours. The suspension was filtered andthe filtrate concentrated under reduced pressure. The residue wasextracted with dichloromethane and water. The organic layer wasextracted with 2N HCl and the aqueous layer basified with 8N NaOH andextracted with dichloromethane. The organic layers were dried overanhydrous Na₂SO₄ and evaporated. The oil obtained (162 mg) was purifiedby HPLC-MS to obtain 4.86 mg (0.015 mmoles) 1.3% of a pure product as aformate, structure confirmed by ¹H-NMR.

1H-NMR (300 MHz, DMSO-d₆): δ 1.86 (m, 4H), 2.65 (s, 2H), 2.77 (bs, 2H),3.03 (bs, 2H), 4.84 (s, 2H), 7.14-7.32 (m, 10H). 8.19 (s, 1H); MS[M-HCOO]⁻: 323.

EXAMPLE 4 Preparation of m-tolyl-(2,4,5-trifluorobenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

0.69 g (30 mmol) of sodium (in small portions) were added to 140 ml ofdry toluene and the suspension was refluxed with vigorous stirring. Whenall the sodium was melted, 3.78 g (29.73 mmol) of(3R)-3-hydroxy-1-azabicyclo[2.2.2]octane were added in five portions,and the-suspension obtained was refluxed for 2 hours, by which time allthe sodium had reacted to form the alcoholate. A solution of 8.11 g(25.85 mmol) of m-Tolyl-(2,4,5-trifluorobenzyl)carbamoyl chloride(Intermediate I-3) in 60 ml of toluene was then slowly added. Themixture obtained was refluxed for 3 hours, and stirred at-roomtemperature for 64 more hours. After this time, the reaction mixture wasfiltered and the solution obtained was extracted with HCl 2N (2×125 ml).The aqueous layers were combined, basified with solid K₂CO₃ andextracted with CHCl₃. The organic layer was dried over anhydrous MgSO₄,filtered and evaporated. The oil obtained (6.30 g) was purified bycolumn chromatography (silica gel, chloroform/ethanol 5:1) to obtain3.05 g (29.2%) of a pure product as an oil, structure confirmed by¹H-NMR.

¹H-NMR (CDCl₃): δ1.22-1.40 (m, 1H), 1.40-1.60 (m, 2H), 1.60-1.75 (m,1H), 2.0 (m, 1H), 2.32 (s, 3H), 2.60-2.90 (m, 5H), 3.17-3.26 (m, 1H),4.78-4.83 (m, 1H), 4.86 (s, 2H), 6.82-7.0 (m, 3H), 7.03-7.07 (m, 1H),7.15-7.25 (m, 2H).

MS [M+1]⁺: 405

EXAMPLE 5 Preparation of[2-4-Fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

A mixture of 0.7 g (0.018 mol) of sodium hydride (60% dispersion inmineral oil) and 1.8 g (0.014 mol) of(3R)-3-hydroxy-1-azabicyclo[2.2.2]octane in 70 ml of toluene wererefluxed for two hours in order to form the alcoholate. A suspension ofa white solid was obtained. A solution of 4.5 g (0.014 mol) of[2-(4-Fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoylchloride in 30 ml of toluene was then slowly added. The mixture obtainedwas refluxed for 2 hours, and stirred at room temperature for 64 hoursmore. After this time, the reaction mixture was cooled to 0-5° C., and75 ml of water were carefully added under stirring. The organic phasewas separated and extracted with HCl 2N (2×75 ml). The aqueous phaseswere combined, basified with NaOH 2N and extracted with toluene (2×75ml). The organic layers were combined and the solution was concentratedto dryness. The oil obtained (1.80 g) was combined with 0.3 g from aprevious preparation and purified by column chromatography (silica gel,CH₂Cl₂/MeOH/NH₄OH 90:10:1 as eluent) to obtain 1.1 g (13.7% globalyield) of the title product as an oil,.structure confirmed by ¹H-NMR.

¹H-NMR (DMSO-d₆): δ 1.33 (m, 1H), 1.48 (m, 1H), 1.60 (m, 2H), 1.89 (m,1H), 2.18 (s, 3H), 2.35-2.85 (m, 7H), 3.07 (m, 1H), 3.20-3.45 (m, 2H),4.45-4.65 (m, 3H), 6.84 (m, 1H), 7.05-7.30 (m, 4H), 7.33 (m, 1H).

MS [M+1]⁺: 403.

[2-(4-Fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoylchloride was prepared according to method (b) starting from thecorresponding amine.

Method (b)

Carbamoyl chlorides of general formula (III) were prepared according toprocedures described in the literature: M. Saraswati et al. DrugDevelopment Research (1994), 31, 142-146; G. M. Shutske et al. J.Heterocycl. Chem. (1990), 27, 1617; GB 1246606; U.S. Pat. No. 2,762,796.

PREPARATION 1 Intermediate I-1—Preparation of butylphenylcarbamoylchloride

To a solution of 6.72 g (45 mmol) of butylphenylamine in 50 ml ofmethylene chloride cooled to 10° C. was added slowly with stirring 6.67g (22.5 mmol) of triphosgene in 40 ml of methylene chloride. Thereaction was allowed to continue at room temperature for 27 hours. Thesolvent was evaporated and the residue extracted twice with n-hexane.The organic solution was concentrated in vacuo to yield 9.11 g (43.03mmol) of a yellow oil (96%). ¹H-NMR (CDCl₃): δ 0.9 (m, 3H), 1.3 (m, 2H),1.6 (m, 2H), 3.7 (m, 2H), 7.2-7.4 (m, 5H).

PREPARATION 2 Intermediate I-2—Preparation ofcyclopentylthiophen-2-ylmethylcarbamoyl chloride

To a solution of 5.0 g (27.58 mmol) ofcyclopentylthiophen-2-ylmethylamine in 40 ml of methylene chloride at10° C. was added slowly with stirring 4.09 g (13.79 mmol) of triphosgenein 35 ml of methylene chloride. The reaction was allowed to continuestirring at room temperature for 64 hours, refluxed for 4 hours and 25hours more at room temperature. The solvent was evaporated and theresidue extracted with n-hexane. The organic solution was concentratedto yield 4.96 g (20.34 mmol) of a brown oil (74%). ¹H-NMR (CDCl₃): δ 1.4(m, 8H), 4.2 (bs, 1H), 4.5 (m, 2H), 6.8-7.3 (m, 3H).

PREPARATION 3 Intermediate I-3—Preparation ofm-tolyl-2,4,-trifluorobenzyl)carbamoyl chloride

To a solution of 6.5 g (25.87 mmol) ofm-tolyl-(2,4,5-trifluorobenzyl)amine (Intermediate I-7) in 45 ml ofmethylene chloride, cooled at −10° C., was added slowly with stirring asolution of 3.84 g (12.94 mmol) of triphosgene in 25 ml of methylenechloride. The reaction was allowed to warm to room temperature, stirredfor 2 hours at this temperature and then refluxed for 10 hours. Afterthis time the solid formed during the process was dissolved. The solventwas evaporated and the residue treated with n-hexane at −25° C. Thesoluble part was separated and filtered. The filtrate was concentratedin vacuo to yield 8.2 g of an oil. The structure was confirmed by¹H-NMR.

¹H-NMR (CDCl₃): δ2.30 (s, 3H), 4.85 (s, 2H), 6.70-7.10 (m, 3H),7.10-7.40 (m, 3H).

PREPARATION 4 Intermediate I-4—Preparation of3-fluorophenyl-(3,4,5-trifluorobenzyl)carbamoyl chloride

To a solution of 3.4 g (13.30 mmol) of3-fluorophenyl-(3,4,5-trifluorobenzyl)amine (Intermediate I-8) in 25 mlof methylene chloride, cooled at −10° C., was added slowly with stirringa solution of 2.0 g (6.70 mmol) of triphosgene in 15 ml of methylenechloride. The reaction was allowed to warm to room temperature andstirred for 17 hours at this temperature. After this time the solidformed during the process was filtered and the filtrate was concentratedin vacuo. The obtained residue was treated with n-hexane at −25° C. Thesoluble part was separated and filtrated. The filtrate was concentratedin vacuo to dryness to give 2.65 g (62.8%) of the tide product as anoil. The structure was confirmed by ¹H-NMR.

¹H-NMR (CDCl₃): δ 4.80 (s, 2H), 6.70-7.0 (m, 4H), 7.0-7.20 (m, 1H),7.25-7.45 (m, 1H).

PREPARATIONS 5-12

Some other examples of compounds of formula (III) that have beenprepared in the present invention according to method (b) are:(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyl chlorideCyclohexylmethyl-(2-fluorophenyl)carbamoyl chloride[2-(3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoylchloride (5-Bromothiophen-2-ylmethyl)-2,4,5-trifluorophenyl)carbamoylchloride(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoylchloride (3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyl chloride(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)carbamoylchloride[2-(4-Fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoylchloride

PREPARATION 13 Intermediate I-5—Preparation of[2-(3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)amine

To a solution of 4.82 g (26.6 mmol) of 2-(3,4-dimethoxyphenyl)ethylamineand 3.0 g (27.2 mmol) of 5-methylfuran-2-carbaldehyde in 65 ml of EtOH,18.3 g of molecular sieves (0.3 nm) were added and the mixture wasrefluxed for 4 hours. After this time the reaction mixture was cooled toroom temperature and filtered. The solution obtained was concentrated invacuo to obtain an oil. This oil was dissolved in 65 ml of MeOH and 1.01g (26.6 mmol) of NaBH₄ were added in small portions, maintaining thetemperature of the reaction at room temperature. The mixture was stirredat this temperature for 16 hours more. After this time the solvent wasevaporated in vacuo and the residue was treated with 150 ml of water andextracted twice with ether. The organic layers were combined, washedwith brine, dried over anhydrous MgSO₄, filtered and evaporated todryness to give 6.05 g (82.6%) of the title product as an oil.

MS [M+1]⁺: 276

¹H-NMR (CDCl₃): δ2.25 (s, 3H), 2.70-2.95 (m, 4H), 3.75 (s, 2H), 3.85(two singlets, 6H), 5.85 (m, 1H), 6.02 (m, 1H), 6.70-6.85 (m, 3H).

PREPARATION 14 Intermediate I-6 Preparation of(5-Bromothiophen-2-ylmethyl)-(2,4,5-trifluorophenyl)amine

To a solution of 2 g (13.6 mmol) of 2,4,5-trifluorophenylamine and 2.66g (13.9 mmol) of 5-bromothiophene-2-carbaldehyde in 30 ml of EtOH, 9.4 gof molecular sieves (0.3 nm) were added and the mixture was refluxed for20 hours. After this time the reaction mixture was cooled to roomtemperature, filtered and the solvent was evaporated in vacuo. The oilobtained was dissolved in 30 ml of MeOH and 0.51 g (13.6 mmol) of NaBH₄were added in small portions, maintaining the temperature of thereaction at room temperature. The mixture was stirred at thistemperature for 20 more hours. After this time the solvent wasevaporated in vacuo and the residue was treated with 100 ml of water andextracted twice with ether. The organic layers were combined, washedwith brine, dried over anhydrous MgSO₄, filtered and evaporated todryness to give 3.2 g of an oil. This 3.2 g were combined with 3.5 gobtained in a subsequent preparation and the total product obtained (6.7g) was purified by chromatography on silica gel using mixtures ofhexane/AcOEt 5:1→1:1 as eluent Appropriate fractions were combined togive 0.95 g of the title product as an oil. (global yield 8.2%).

MS [M+1]⁺: 321,323

¹H-NMR (CDCl₃): δ4.10 (bs, NH, 1H), 4.40 (s, 2H), 6.40-6.65 (m, 1H),6.75-7.10 (m, 3H).

PREPARATION 15 Intermediate I-7—Preparation ofm-Tolyl-(2,4,5-fluorobenzyl)amine

To a solution of m-tolylamine (3.26 g, 3.27 ml, 30.5 mmol) and2,4,5-trifluorobenzaldehyde (5.0 g, 31.2 mmol) in 60 ml of EtOH, 21 g ofmolecular sieves (0.3 nm) were added and the mixture was refluxed for 3hours. After this time the reaction mixture was cooled to roomtemperature and filtered. The solution obtained was concentrated invacuo to obtain an oil. This oil was dissolved in 60 ml of MeOH and 1.15g (30.5 mmol) of NaBH₄ were added in small portions, maintaining thetemperature of the reaction at room temperature. The mixture was stirredat this temperature for 16 hours more. After this time the solvent wasevaporated in vacuo and the residue was treated with 100 ml of water andextracted twice with ether. The organic layers were combined, washedwith brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo to dryness to give 6.5 g (84.8%) of the title product as an oil(that solidified at low temperature). The structure was confirmed by¹H-RMN and MS.

GC/MS: [M]⁺: 251

¹H-NMR (CDCl₃): δ 2.25 (s, 3H), 4.0 (bs, 1H), 4.35 (s, 2H), 6.35-6.65(m, 3H), 6.85-7.40 (m, 3H).

PREPARATION 16 Intermediate I-8—Preparation of(3-Fluorophenyl)-(3,4,5trifluorobenzyl)amine

A mixture of 3.7 g (3.2 ml, 33.3 mmol) of 3-fluorophenylamine, 2.5 g(11.1 mmol) of 5-(bromomethyl)-1,2,3-trifluorobenzene and 1.53 g (11.1mmol) of K₂CO₃ in 30 ml of toluene, was refluxed during 5 h and stirredat room temperature during 16 hours more. After this time the mixture ofreaction was filtered and the solid obtained was washed with toluene.The toluene solutions were combined, washed with water and brine, driedover MgSO₄, and concentrated in vacuo to dryness to give 5.0 g of anoily residue. This oil was treated with diethyl ether and the obtainedsolid was separated by filtration and discarded. The filtrate wasconcentrated to dryness and purified by Kugelrohr distillation atreduced pressure. After distillation of the excess of3-fluorophenylamine (0.15 mm Hg, 100° C. oven), 2.40 g (84.8%) of thetitle product were distilled (0.15 mm Hg, 175-200° C. oven). Structureconfirmed by MS and ¹H-RMN.

GC/MS: [M]⁺: 255

¹H-NMR (CDCl₃): δ 4.30 (s, 2H), 4.0-4.50 (bs, 1H), 6.20-6.55 (m, 3H),6.80-7.25 (m, 3H).

3-fluorophenyl-(3,4,5-trifluorobenzyl)amine has also been prepared byreductive alkylation starting from 3,4,5-trifluorobenzaldehyde and3-fluorophenylamine.

PREPARATIONS 17-22

Some other examples of compounds of formula (V) that have been preparedin the present invention are: (3-Fluorobenzyl)-(3-fluorophenyl)amineCyclohexylmethyl-(2-fluorophenyl)amine(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)amine(3-Fluoro-4-ethoxyphenyl)thiophen-3-ylmethylamine(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)amine[2-(4-Fluorophenyl)ethyl](3-methylthiophen-2-ylmethyl)amine

Method (c)

EXAMPLE 6 Preparation of(3R)-3-bis-thiophen-2-ylmethylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane,bromide

0.54 g (1.5 mmol) of bis-thiophen-2-ylmethylcarbamic add(3R)-1-azabicyclo[2.2.2]oct-3-yl ester, 7.5 ml of tetrahydrofuran and0.46 g (2.25 mmol) of 2-(3-bromopropyl)thiophene were mixed. Thesolution was refluxed for 4 hours and stirred at room temperature for116 hours. Ether was added and the suspension was stirred for 30 min.The solvent was extracted and more ether was added. This procedure wasrepeated several times in order to eliminate the alkylating agent.Finally the suspension was filtered and the residue dried in the vacuumoven. The yield was 0.69 g (1.22 mmol) (81%).

¹H-NMR (DMSO-d₆): 1.78-2.10 (m, 6H), 2.34 (bs, 1H), 2.82 (m, 2H),3.21-3.46 (m, 7H), 3.89 (m, 1H), 4.54 (m, 4H), 5.06 (m, 1H), 6.95-7.01(m, 4H), 7.07-7.11 (m, 2H), 7.38-7.49 (m, 3H); MS [M-Br]⁺: 487; mp: 143°C.

EXAMPLE 7 Preparation of(3R)-1-(2-phenoxyethyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide

0.300 g (0.742 mmol) of m-tolyl-(2,4,5-trifluorobenzyl)carbamic add(3R)-1-azabicyclo[2.2.2]oct-3-yl ester, 7.0 ml of tetrahydrofuran and0.253 g (1.258 mmol) of (2-bromoethoxy)benzene were mixed. Thesolution-was refluxed for 55 hours and allowed to continue stirring atroom temperature during 16 more hours. After this time the solvent wasevaporated in vacuo. Ether was added and the mixture stirred to obtain asolid. This solid was treated with ether several times in order toeliminate the residual alkylating agent. Finally the suspension wasfiltered and the solid obtains washed with ether and dried. The yieldwas 0.34 g (75.5%).

m.p.: 137.3-139.1° C.

MS [M-Br]⁺: 525

¹H-NMR(DMSO-d₆): δ1.40-1.70 (m, 1H), 1.70-2.05 (m, 3H), 2-20 (m, 1H),2.25 (s, 3H), 3.25-3.40 (m, 1H), 3.40-3.80 (m, 6H), 3.95-4.10 (m, 1H),4.44 (m, 2H), 4.90 (m, 2H), 5.01 (m, 1H), 6.95-7.30 (m, 7H), 7.30-7.60(m, 4H).

EXAMPLE 8 Preparation of(3R)-1-Allyl-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide

0.300 g (0.7 mmol) of[2-3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester were dissolved in 5 ml of CHCl₃and 3.5 ml of acetonitrile. To this solution 0.30 ml (0.423 g, 3.5 mmol)of allyl bromide were added and the mixture was stirred during 21 hoursat room temperature under N₂ atmosphere. Solvents were evaporated. Theresidue was treated with ether several times to obtain an oil, which wasredissolved in CHCl₃ and evaporated to dryness to give 0.365 g (94.8%)of the title producl

MS [M-Br]⁺: 469

Method (d)

EXAMPLE 9 Preparation of(3R)-1-heptyl-3-(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

30 mg (0.08 mmols) of phenylthiophen-3-yl methyl carbamic add(3R)-1-azabicyclo[2.2.2]oct-3-yl ester were dissolved in 1 ml of DMSO.To this solution 75 mg (0.40 mmol) of heptyl bromide were added. Afterstirring overnight at room temperature, the mixture was purified bysolid phase extraction with a cation exchange Mega Bond Elut cartridge,previously conditioned at pH=7.5 with 0.1 M NaH₂PO₄ buffer. The reactionmixture was applied to the cartridge and washed first with 2 ml of DMSOand then three times with 5 ml of CH₃CN, rinsing away all startingmaterials. The ammonium derivative was eluted with 5 ml of 0.03 M TFAsolution in CH₃CN:CHCl₃ (2:1). This solution was neutralized with 300 mgof poly(4-vinylpyridine), filtered and evaporated to dryness.

The yield was 12 mg (34%) of title compound. ¹H-NMR (DMSO-d₆): δ 0.88(m, 3H), 1.28 (m, 8H), 1.60-2.19 (m, 7H), 3.00-3.41 (m, 7H), 3.83 (m,1H), 4.88 (s, 2H), 5.99 (m, 1H), 7.01 (m, 1H), 7.21-7.39 (m, 6H),7.49-7.52 (m, 1H); MS [M-CF₃COO]⁺: 441

Also included within the scope of the present invention arepharmaceutical compositions which comprise, as the active ingredient, atleast one quinuclidine derivative of general formula (I) or (II) inassociation with a pharmaceutically acceptable carrier or diluent.Preferably the composition is made up in a form suitable for oraladministration.

The pharmaceutically acceptable carrier or diluents which are mixed withthe active compound or compounds, to form the composition of thisinvention are well-known per se and the actual excipients used dependinter alia on the intended method of administration of the composition.

Compositions of this invention are preferably adapted for oraladministration. In this case, the composition for oral administrationmay take the form of tablets, film-coated tablets, liquid inhalant,powder inhalant and inhalation aerosol; all containing one or morecompounds of the invention; such preparations may be made by methodswell-known in the art.

The diluents which may be used in the preparations of the compositionsinclude those liquid and solid diluents which are compatible with theactive ingredient, together with colouring or flavouring agents, ifdesired. Tablets or film-coated tablets may conveniently contain between0.1 mg and 500 mg, preferably from 0.5 to 200 mg of active ingredient.The inhalant compositions may contain between 1 μg and 1,000 μg,preferably from 10 to 800 μg of active ingredient In human therapy, thedose of the compound of general formula (I) or (II) will depend on thedesired effect and duration of treatment; adult doses are generallybetween 0.5 mg and 300 mg per day as tablets and 10 μg and 800 μg perday as inhalant composition.

The compounds of the present invention, or pharmaceutical compositionscontaining them, may be used together with a β₂ agonist, steroid,antiallergic drug and/or phosphodiesterase IV inhibitor, forsimultaneous, separate or sequential use in the treatment of arespiratory disease.

Pharmacological Action

The following examples demonstrate the excellent pharmacologicalactivities of the compounds of the present invention. The results onhuman muscarinic receptor binding and in the test on bronchospasm inguinea pig, were obtained as described below.

Human Muscarinic Receptor Studies.

The binding of [³H]-NMS to human muscarinic receptors was performedaccording to Waelbroeck et al (1990), Mol. Pharmacol., 38: 267-273.Assays were carried out at 25° C. Membrane preparations from stablytransfected Chinese hamster ovary-K1 cells (CHO) expressing the genesfor the human muscarinic M3 receptors were used.

For determination of IC₅₀, membrane preparations were suspended in DPBSto a final concentration of 89 μg/ml for the M3 subtype. The membranesuspension was incubated with the tritiated compound for 60 min. Afterincubation the membrane fraction was separated by filtration and thebound radioactivity determined. Non specific binding was determined byaddition of 10⁻⁴ M atropine. At least six concentrations were assayed induplicate to generate individual displacement curves. Our results showthat the compounds of the present invention have high affinities formuscarinic M3 receptors. Preferred compounds of the invention have anIC₅₀ (nM) value for M3 receptors of less than 35 nM, most preferablyless than 10 nM.

The preferred compounds of the invention also show high selectivity forM3 receptors with respect to M2 receptors. Thus, the ratio IC₅₀ M2/IC₅₀M3 is higher than 5, preferably higher than 10, most preferable higherthan 15.

Test on Bronchospasm in Guinea Pig

The studies were performed according to H. Konzett and F. Rössler(1940), Arch. Exp. Path. Pharmacol. 195, 71-74. Aqueous solutions of theagents to be tested were nebulized and inhaled by anaesthetizedventilated male guinea pigs (Dunkin-Hartley). Bronchial response tointravenous acetylcholine challenge was determined before and after drugadministration and changes in pulmonary resistance at severaltime-points were expressed as percent of inhibition of bronchospasm.

The compounds of the present invention showed bronchodilator activitywith high potency and a long duration of action.

From the above described results one of ordinary skill in the art canreadily understand that the compounds of the present invention haveexcellent antimuscarinic activity (M3) and thus are useful for thetreatment of diseases in which the muscarinic M3 receptor is implicated,including respiratory diseases such as chronic obstructive pulmonarydisease, bronchitis, asthma, bronchial hyper reactivity and rhinitis;urinary diseases such as urinary incontinence, pollakiuria, neurogenicbladder, nocturnal enuresis, unstable bladder, cystospasm and chroniccystitis; gastrointestinal diseases such as irritable bowel syndrome,spastic colitis, diverticulitis and peptic ulceration; andcardiovascular disorders such as vagally induced sinus bradicardia. Forexample, the compounds of the present invention are useful for thetreatment of respiratory diseases such as chronic obstructive pulmonarydisease, chronic bronchitis, asthma, and rhinitis; urinary diseases suchas urinary incontinence and pollakinuria in neuripenia pollakinuria,neurogenic bladder, nocturnal enuresis, unstable bladder, cytospasm andchronic cystitis; and gastrointestinal diseases such as irritable bowelsyndrome, spastic colitis and diverticulitis.

The present invention further provides a compound of formula (I) or (II)or a pharmaceutically acceptable composition comprising a compound offormula (I) or (II) for use in a method of treatment of the human oranimal body by therapy, in particular for the treatment of respiratory,urinary or gastrointestinal disease.

The present invention further provides the use of a compound of formula(I) or (II) or a pharmaceutically acceptable composition comprising acompound of formula (I) or (I) for the manufacture of a medicament forthe treatment of respiratory, urinary or gastrointestinal disease.

Further, the compounds of formula (I) or (II) and pharmaceuticalcompositions comprising a compound of formula (I) or (II) can be used ina method of treating respiratory, urinary or gastrointestinal disease,which method comprises administering to a human or animal patient inneed of such treatment an effective amount of a compound of formula (I)or (II) or a pharmaceutical composition comprising a compound of formula(I) or (II).

Further, the compounds of formula (I) or (II) and pharmaceuticalcompositions comprising a compound of formula (I) or (II) can be used incombination with other drugs effective in the treatment of thesediseases. For example with β₂ agonists, steroids, antiallergic drugs,phosphodiesterase IV inhibitors and/or leukotriene D4 (LTD4) inhibitors,for simultaneous, separate or sequential use in the treatment of arespiratory disease.

The present invention therefore provides a combination productcomprising

-   -   (i) a compound according to the invention; and    -   (ii) another compound effective in the treatment of a        respiratory, urological or gastrointestinal disease or disorder    -   for simultaneous, separate or sequential use.

The compound (ii) which is effective in the treatment of a respiratory,urological or gastrointestinal disease or disorder may be a β₂ agonist,steroid, antiallergic drug, phosphodiesterase IV inhibitor and/orleukotriene D4 (LTD4) antagonist Preferably, the product is forsimultaneous, separate or sequential use in the treatment of arespiratory disease.

The present invention will be further illustrated by the followingexamples. The examples are given by way of illustration only and are notto be construed as limiting.

EXAMPLE 10 (3-Fluorobenzyl)-(3-fluorophenyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a. The yield was3.0 g, 39.1%.

MS [M+1]⁺: 373

¹H-NMR(CDCl₃): δ 1.20-1.35 (m, 1H), 1.35-1.50 (m, 1H), 1.5-1.60 (m, 1H),1.60-1.75 (m, 1H), 2.0 (m, 1H), 2.55-2.85 (m, 5H), 3.18-3.27 (m, 1H),4.79-4.90 (m, 1H), 4.90 (s, 2H), 6.85-7.10 (m, 5H), 7.22-7.35 (m, 3H).

EXAMPLE 11(3R)-3-[(3-Fluorobenzyl)-3-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.32 g, 69.2%.

m.p.: 142.8-143.6° C.

MS [M-Br]⁺: 493

¹H-NMR(DMSO-d₆): δ1.50-1.70 (m, 1H), 1.70-1.85 (m, 1H), 1.85-2.05 (m,2H), 2.23 (m, 1H), 3.25-3.40 (m, 1H), 3.40-3.75 (m, 6H), 3.95-4.10 (m,1H), 4.44 (m, 2H), 4.90-5.10 (m, 3H), 6.90-7.25 (m, 8H), 7.25-7.45 (m,5H).

EXAMPLE 12(3R)-3-[(3-Fluorobenzyl)-3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.24 g, 52.1%.

m.p.: 64.5-66.0° C.

MS [M-Br]⁺: 491

¹H-NMR(DMSO-d₆): δ1.50-1.65 (m, 1H), 1.65-1.80 (m, 1H), 1.80-2.10 (m,4H), 2.20 (m, 1H), 2.60 (t, 2H), 3.05-3.55 (m, 7H), 3.80-3.90 (m, 1H),4.90-5.10 (m, 3H), 7.05-7.45 (m, 13H).

EXAMPLE 13(3R)-1-(3-Phenylpropyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.32 g, 72.5%.

m.p.: 113.1-114.8° C.

MS [M-Br]⁺: 523

¹H-NMR(DMSO-d₆): δ1.40-1.60 (m, 1H), 1.60-1.80 (m, 1H), 1.80-2.10 (m,4H), 2.18 (m, 1H), 2.26 (s, 3H), 2.60 (t, 2H), 3.05-3.55 (m, 7H),3.80-3.90 (m, 1H), 4.90 (m, 2H), 4.98 (m, 1H), 7.0-7.15 (m, 2H),7.15-7.40 (m, 7H), 7.40-7.60 (m, 2H).

EXAMPLE 14 (3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a. The yield was0.33 g, 8.8%.

MS [M+1]⁺: 409

¹H-NMR(CDCl₃): δ1.20-1.80 (m, 4H), 2.02 (m, 1H), 2.60-3.05 (m, 5H),3.25-3.40 (m, 1H), 4.70-4.82 (m, 2H), 4.85-4.90 (m, 1H), 6.80-7.10 (m,4H), 7.20-7.40 (m, 2H).

EXAMPLE 15(3R)-3-[(3-Fluorophenyl)-3,4,5-trifluorobenzyl)carbamoyloxy]-1-2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.16 g, 75%.

m.p.: 173.9-175.5° C.

MS [M-Br]⁺: 529

¹H-NMR(DMSO-d₆): δ1.50-2.05 (m, 4H), 2.24 (m, 1H), 3.25-3.85 (m, 7H),4.03 (m, 1H), 4.45 (m, 2H), 4.95 (m, 2H), 5.04 (m, 1H), 6.95-7.15 (m,4H), 7.20-7.45 (m, 7H).

EXAMPLE 16 Cyclohexylmethyl-(2-fluorophenyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a. The yield was3.15 g, 42.3%.

MS [M+1]⁺: 361

¹H-NMR(CDCl₃): δ 0.80-1.05 (m, 2H), 1.05-1.80 (m, 13H), 2.0 (m, 1H),2.55-3.05 (m, 5H), 3.15-3.30 (m, 1H), 3.40-3.60 (m, 2H), 4.70-4.85 (m,1H), 7.05-7.35 (m, 4H).

EXAMPLE 17(3R)-3-[Cyclohexylmethyl-(2-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.38 g, 81.4%.

m.p.: 73.1-74.5° C.

MS [M-Br]⁺: 481

¹H-NMR(DMSO-d₆): δ0.80-1.0 (m, 2H), 1.0-1.20 (m, 3H), 1.20-1.45 (m, 1H),1.45-1.80 (m, 6H), 1.80-2.20 (m, 4H), 3.05-3.20 (m, 1H), 3.30-3.85 (m,8H), 3.90-4.10 (m, 1H), 4.35-4.50 (m, 2H), 4.90-5.10 (m, 1H), 6.95-7.10(m, 3H), 7.20-7.55 (m, 6H).

EXAMPLE 18(3R)-3-[Cyclohexylmethyl-(2-fluorophenyl)carbamoyloxy-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.34 g, 73%.

m.p.: 73.3-74.1° C.

MS [M-Br]⁺: 479

¹H-NMR(DMSO-d₆): δ 0.80-1.45 (m, 6H), 1.50-2.20 (m, 12H), 2.57 (m, 2H),2.90-3.0 (m, 1H), 3.10-3.65 (m, 8H), 3.75-3.95 (m, 1H), 4.90-5.05 (m,1H); 7.20-7.55 (m, 9H).

EXAMPLE 19[2-(3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a. The yield was3.5 g, 61.2%.

MS [M+1]⁺: 429

¹H-NMR(CDCl₃): δ 1.34-1.50 (m, 1H), 1.50-1.64 (m, 1H), 1.64-1.78 (m,1H), 1.78-1.94 (m, 1H), 2.05 (m, 1H), 2.27 (two singlets, 3H), 2.64-2.84(m, 5H), 2.84-2.98 (m, 2H), 3.20-3.30 (m, 1H), 3.35-3.60 (m, 2H), 3.82(s, 6H), 4.28 (m, 1H), 4.36 (m, 1H), 4.76 (m, 1H), 5.89 (m, 1H),6.03-6.13 (m, 1H), 6.60-6.82 (m, 3H).

EXAMPLE 20(3R)-3-[[2-(3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octaneformate

The title compound was synthesised according to methods a and c. Thealkylating agent used in method c was ethyl 5-bromopentanoate.

A portion of 270 mg of the obtained product was purified by preparativeHPLC/MS to give 53 mg of the pure product as a formate.

MS [M-HCOO⁻]⁺: 557

¹H-NMR (DMSO-d₆): δ 1.16-1.23 (m, 3H), 1.45-1.75 (m, 4H), 1.75-2.10 (m,4H), 2.14-2.28 (m, 1H), 2.24 (s, 3H); 2.38 (m, 2H), 2.68 (m, 2H),3.0-3.90 (m, 10H), 3.71 and 3.73 (two singlets, 6H), 4.03-4.10 (m, 2H),4.31-4.48 (m, 2H), 4.80-5.0 (m, 1H), 6.03 (m, 1H); 6.27 (m, 1H),6.64-6.88 (m, 3H), 8.34 (s, 1H).

Conditions used in the purification HPLC-MS:

Column: Symmetry C18, 100 A, 5 μm 19×100 mm, Waters.

Mobile phase: A (H₂O 0.1% HCOONH₄, pH=3) and B (AcN 0.1% HCOONH₄, pH=3),B: 19%→34%.

EXAMPLE 21 (5-Bromothiophen-2-ylmethyl)-(2,4,5-trifluorophenyl)carbainicacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a.

A portion of 158 mg of the obtained product was purified by preparativeHPLC/MS to give 16 mg of pure product as a formate.

MS [M+1]⁺: 475, 477

Conditions used in the purification HPLC-MS:

Column: Symmetry C18, 100 A, 5 μm 19×100 mm, Waters.

Mobile phase: A (H₂O 0.1% HCOONH₄, pH=3) and B (AcN 0.1% HCOONH₄, pH=3),B: 10%→35%.

EXAMPLE 22(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 0.8 g, 10.8%.

MS [M+1]⁺: 389

¹H-NMR (CDCl₃): δ 1.10-1.25 (m, 2H), 1.45-1.70 (m, 2H), 1.70-1.85 (m,1H), 1.87 (s, 3H), 2.0-2.05 (two singlets, 3H), 2.40-3.0 (m, 5H),3.10-3.40 (m, 1H), 4.65-5.0 (m, 3H), 6.72 (m, 1H), 6.80-6.95 (m, 3H),7.12 (m, 1H).

EXAMPLE 23(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.5 g, 84.7%.

MS [M-Br]⁺: 509

¹H-NMR(DMSO-d₆): δ 1.15-1.45 (m, 1H), 1.60-2.20 (m, 10H), 2.90-3.10 (m,1H), 3.30-3.85 (m, 6H), 3.90-4.20 (m, 1H), 4.30-4.55 (m, 2H), 4.75-5.15(m, 3H), 6.78 (m, 1H), 6.90-7.20 (m, 6H), 7.35 (m, 3H).

EXAMPLE 24 (3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a The yield ofthe final step was 1.9 g, 25.7%.

MS [M+1]⁺: 391

¹H-NMR (CDCl₃): δ 1.20-1.90 (m, 4H), 2.01 (m, 1H), 2.55-2.90 (m, 5H),3.22 (m, 1H), 3.88 (s, 3H), 4.70-4.90 (m, 3H), 6.70-6.95 (m, 3H),6.95-7.15 (m, 2H), 7.26 (m, 1H).

EXAMPLE 25(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 1.9 g, 97.1%

MS [M-Br]⁺: 507

¹H-NMR(DMSO-d₆): δ 1.40-1.65 (m, 1H), 1.65-2.05 (m, 3H), 2.10-2.30 (m,1H), 3.10-3.30 (m, 1H), 3.30-3.60 (m, 4H), 3.78 (s, 3H), 3.80-3.95 (m,1H), 3.95-4.10 (m, 2H), 4.80 (m, 2H), 5.0 (m, 1H), 6.42 (m, 1H), 6.85(m, 1H), 6.90-7.15 (m, 3H), 7.20-7.50 (m, 7H), 7.58 (m, 1H).

EXAMPLE 26(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The title compound was synthesised according to method a. 200 mg of theobtained product were purified by column chromatography (silica gel,CHCl₃/EtOH 5:1 as eluent) to obtain 34 mg of a pure sample.

MS [M+1]⁺: 373

¹H-NMR (CDCl₃): δ 1.20-1.40 (m, 1H), 1.40-1.55 (m, 1H), 1.55-1.70 (m,1H), 1.70-1.80 (m, 1H), 1.85-2.05 (m, 1H), 1.90 (s, 3H), 2.16 (s, 3H),2.25 (s, 3H), 2.70-3.05 (m, 5H), 3.25-3.32 (m, 1H), 4.20-4.50 (m, 4H),4.85 (m, 1H), 5.85-5.15 (m, 3H).

EXAMPLE 27(3R)-1-Allyl-3-[2-(4-fluorophenylethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods a and c. Theyield of the final step was 0.4 g, 51.3%.

MS [M-Br]⁺: 443

¹H-NMR(DMSO-d₆) δ 1.80-2.10 (m, 4H), 2.20 (s, 3H), 2.25-2.30 (m, 1H),2.77 (m, 2H), 3.15-3.70 (m, 7H), 3.82 (m, 1H), 3.90 (m, 2H), 4.45-4.65(m, 2H), 4.85-5.05 (m, 1H), 5.56-5.66 (m, 2H), 5.90-6.10 (m, 1H), 6.87(m, 1H), 7.10-7.30 (m, 4H), 7.36 (m, 1H).

EXAMPLE 28

Benzylphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 1000 mg, 18%. ¹H-NMR (CDCl₃): δ 1.3-1.7 (m, 4H), 1.9(s, 1H), 2.5-2.8 (m, 5H), 3.2 (m, 1H), 4.8 (m, 1H), 4.9 (s, 2H), 7.1-7.4(m, 10H); MS [M+1]⁺: 337.

EXAMPLE 293-(R)(Benzylphenylcarbamoyloxy)-1-methyl-1-azoniabicyclo[2.2.2]octane,trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 20 mg, 34%. ¹H-NMR (DMSO-d₆): δ 1.54-1.90 (m, 4H),2.17 (s, 1H), 2.95 (s, 3H), 3.22-3.52 (m, 5H), 3.84 (m, 1H), 4.92 (s,2H), 4.99 (m, 1H), 7.12-7.37 (m, 10H); MS [M-CF₃COO]⁺: 351.

EXAMPLE 303-(R)(Benzylphenylcarbamoyloxy)-1-(4-methylpent-3-enyl)-1-azoniabicyclo[2.2.2]octane,trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 18 mg, 25%. MS [M-CF₃COO]⁺: 419.

EXAMPLE 313-(R)(Benzylphenylcarbamoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 21 mg, 26%. ¹H-NMR (DMSO-d₆): δ 1.56-1.91 (m, 4H),2.11-2.20 (m, 3H), 3.12 (m, 1H), 3.34-3.51 (m, 6H), 3.86 (m, 1H), 4.06(m, 2H), 4.93 (s, 2H), 5.02 (m, 1H), 6.97 (m, 3H), 7.20-7.38 (m, 12H);MS [M-CF₃COO]⁺: 471.

EXAMPLE 323-(R)(Benzylphenylcarbamoyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 220 mg, 70%. ¹H-NMR (DMSO-d₆): δ 1.55-1.92 (m, 4H),2.21 (s, 1H), 3.15 (m, 1H), 3.34-3.50 (m, 5H), 3.90 (m, 1H), 4.1 (m, 2H), 4.02 (s, 2 H), 5.05 (m, 1H), 6.49 (m, 1H), 6.85-6.90 (d, 1H),7.20-7.59 (m, 12H), 7.59-7.61 (m, 2H); MS [M-Br]⁺: 453; mp: 129° C.

EXAMPLE 331-Allyl-3-(R)(benzylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 230 mg, 85%. ¹H-NMR (DMSO-d₆): δ 1.58-1.91 (m, 4H),2.20 (s, 1H), 3.10 (m, 1H), 3,10 (m, 1H), 3.27-3.41 (m, 4H), 3.79-3.90(m, 3H), 4.92 (s, 2H), 5.03 (m, 1H), 5.61 (m, 2H), 5.98 (m, 1H),7.20-7.38 (m, 10H); MS [M-Br]⁺: 377; mp: 70° C.

EXAMPLE 343-(R)(Benzylphenylcarbamoyloxy)-1-(2-hydroxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 19%. MS [M-CF₃COO]⁺: 381.

EXAMPLE 353-(R)(Benzylphenylcarbamoyloxy)-1-isopropyl-1-azoniabicyclo[222]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 17 mg, 26%. ¹H-NMR (DMSO-d₆): δ 1.24 (m, 6H),1.64-1.89 (m, 4H), 2.20 (s,1H), 2.78 (m,1H), 3.23-3.32 (m,4 H), 3.50 (m,1H), 3.76 (m, 1H), 4.92 (s, 2H), 5.06 (m, 1H), 7.20-7.38 (m,10H); MS[M-CF₃COO]⁺: 379.

EXAMPLE 363-(R)(Benzylphenylcarbamoyloxy)-1-propyl-1-azoniabicyclo[2.2.2 octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 25%. ¹H-NMR (DMSO-d₆): δ 0.88 (m, 3H),1.57-1.68 (m, 4H), 1.89 (m, 2H), 2.18 (s, 1H), 2.99-3.14 (m, 3H),3.26-3.40 (m, 4H), 3.83 (m,1H), 4.92 (s, 2H), 5.01 (m, 1H), 7.20-7.37(m, 10H); MS [M-CF₃COO]⁺: 379.

EXAMPLE 373-(R)(Benzylphenylcarbamoyloxy)-1-(3-cyanopropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d: The yield ofthe final step was 13 mg, 19%. ¹H-NMR (DMSO-d₆): δ 1.67-2.07 (m, 6H),2.19 (s, 1H), 2.60 (m,2H), 3.07 (m, 1H), 3.21-3.48 (m, 6H), 3.85 (m,1H),4.92 (s, 2H), 5.01 (m,1H), 7.20-7.37 (m, 10); MS [M-CF₃COO]⁺: 404.

EXAMPLE 383-(R)(Benzylphenylcarbamoyloxy)-1-cyclopropylmethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 9 mg, 14%. MS [M-CF₃COO]⁺: 391.

EXAMPLE 393-(R)(Benzylphenylcarbamoyloxy)-1-(2-ethoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 22 mg, 32%. ¹H-NMR (DMSO-d₆): δ 1.12 (m, 3H):1.58-1.90 (m, 4H), 2.19 (s, 1H), 3.12-3.15 (m,1H), 3.28-3.53 (m, 8H),3.75 (m, 2H), 3.90 (m,1H), 4.91 (s, 2H), 5.02 (m,1H), 7.20-7.37 (m,10H); MS [M-CF₃COO]⁺: 409.

EXAMPLE 403-(R)(Benzylphenylcarbamoyloxy)-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 18%. ¹H-NMR (DMSO-d₆): δ 1.19 (m, 3H),1.50-1.67 (m, 4H), 1.85-1.88 (m, 2H), 2.18 (s,1H), 2.38 (m, 2H), 3.99(m,1H), 3.16-3.42 (m, 8H), 3.82 (m, 1H), 4.06 (m, 2H), 4.92 (s, 2H),5.02 (m, 1H), 7.19-7.37 (m, 10H); MS [M-CF₃COO]⁺: 465.

EXAMPLE 413-(R)(Benzylphenylcarbamoyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 18%. ¹H-NMR (DMSO-d₆): δ 1.57-1.65 (m, 6H),1.88 (m, 2H), 2.18 (s, 1H), 2.63 (m, 2H), 3.00 (m, 1H), 3.18-3.42 (m,6H), 3.79-3.86 (m, 1H), 4.94 (s, 2H), 5.00 (m, 1H), 7.18-7.37 (m, 15H);MS [M-CF₃COO]⁺: 469.

EXAMPLE 423-(R)(Benzylphenylcarbamoyloxy)-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 21 mg, 25%. ¹H-NMR (DMSO-d₆): δ 1.55-1.91 (m, 4H),2.10-2.20 (m,3H), 3.10 (m, 1H), 3.28-3.50 (m, 6H), 3.88 (m,1H), 4.02 (m,2H), 4.93 (s, 2H), 5.02 (m, 1H), 6.95-7.12 (m, 2H), 7.12-7.38 (m,12H);MS [M-CF₃COO]⁺: 489.

EXAMPLE 433-(R)(Benzylphenylcarbamoyloxy)-1-(3-hydroxypropyl)-1-azoniabicyclo[2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 18%. ¹H-NMR (DMSO-d₆): δ 1.54-1.88 (m, 6H),2.18 (s, 1H), 3.09 (m, 1H), 3.23-3.49 (m, 8H), 3.85 (m, 1H), 4.84(m,OH), 4.92 (s, 2H), 5.02 (m, 1H), 7.19-7.37 (m, 10H); MS [M-CF₃COO]⁺:395.

EXAMPLE 441-(4-Acetoxybutyl)-3-(R)(benzylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 9 mg, 12%. ¹H-NMR (DMSO-d₆): δ 1.40-1.70 (m, 5H),1.81-1.91 (m, 3H), 2.02 (m, 3H), 2.19 (s, 1H), 3.03 (m, 1H), 3.19 (m,2H), 3.26-3.46 (m, 4H), 3.80-3.84 (m, 1H), 4.04 (m, 2H), 4.92 (s, 2H),5.01-5.02 (m, 1H), 7.19-7.37 (m, 10H); MS [M-CF₃COO]⁺: 451.

EXAMPLE 453-(R)(Benzylphenylcarbamoyloxy)-1-(4-oxo-4-thiophen-2-ylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 19%. ¹H-NMR (DMSO-d₆): δ 1.55-1.69 (m, 2H),1.87-2.05 (m, 4H), 2.19 (s, 1H), 3.09 (m, 3H), 3.22 (m, 2H), 3.29-3.46(m, 4H), 3.88 (m, 1H), 4.93 (s, 2H), 5.02 (m, 1H), 7.19-7.38 (m, 11H),7.98-8.06 (m, 2H); MS [M-CF₃COO]⁺: 489.

EXAMPLE 463-(R)(Benzylphenylcarbamoyloxy)-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 17 mg, 21%. ¹H-NMR (DMSO-d₆): δ 1.57-1.68 (m, 2H),1.90 (m, 2H), 2.08-2.19 (m, 3H), 3.11 (m, 1H), 3.28-3.50 (m, 6H), 3.88(m, 1H), 3.97 (m, 2H), 4.93 (s, 2H), 5.02 (m, 1H), 6.33-6.40 (m, 3H),7.04 (m,1H), 7.20-7.38 (m, 10H), 9.5 (s, OH); MS [M-CF₃COO]⁺: 487.

EXAMPLE 473-(R)(Benzylphenylcarbamoyloxy)-1-heptyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 17 mg, 23%. ¹H-NMR (DMSO-d₆): δ 0.88 (m, 3H), 1.28(m, 8H), 1.62 (m, 4H), 1.85-1.88 (m, 2H), 2.18 (s, 1H), 3.02 (m, 1H),3.15 (m, 2H), 3.26-3.40 (m, 4H), 3.83 (m, 1H), 4.92 (s, 2H), 5.01 (m,1H), 7.20-7.37 (m, 10H); MS [M-CF₃COO]⁺: 435.

EXAMPLE 481-(2-Benzyloxyethyl)-3-(R)(benzylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 20 mg, 25%. ¹H-NMR (DMSO-d₆): δ 1.54-1.94 (m, 4H),2.20 (s, 1H), 3.17 (m, 1H), 3.28-3.55 (m, 6H), 3.85 (m, 2H), 9.92-3.99(m, 1H), 4.53 (s, 2H), 4.91 (s, 2H), 5.02 (m, 1H), 7.18-7.40 (m, 15H);MS [M-CF₃COO]⁺: 471.

EXAMPLE 49 Benzyl-(4-fluorophenyl)carbamic acid1-azabicyclo[2.2.2]oct-3(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 1110 mg, 13%. ¹H-NMR (DMSO-d₆): δ 1.16-1.52 (m, 4H),1.81 (s, 1H), 2.42-2.57 (m, 5H), 2.99-3.07 (m, 1H), 4.63 (m, 1H), 4.84(s, 2H), 7.10-7.32 (m, 9H); MS [M+1]: 355.

EXAMPLE 501-Allyl-3-(R)[benzyl-4-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10mg, 23%. MS [MC-F₃COO]⁺: 395.

EXAMPLE 513-(R)[Benzyl-(4-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 25%. MS [MC-F₃COO]⁺: 473.

EXAMPLE 52 Benzyl-p-tolylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)ylester

The title compound was synthesised according to method a. The yield ofthe final step was 1070 mg, 11%. ¹H-NMR (DMSO-d₆): δ 1.18-1.30 (m, 2H),1.45-1.55 (m, 2H), 1.83 (s, 1H), 2.25 (s, 3H), 2.43-2.59 (m,5H),3.01-3.10 (m, 1H), 4.64 (m, 1H), 4.85 (s, 2H), 7.12-7.34 (m, 9H); MS[M+1]⁺: 351.

EXAMPLE 531-Allyl-3-(R)(benzyl-p-tolyl-carbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 9 mg, 19%. MS [M-CF₃COO]⁺: 391.

EXAMPLE 543-R)(Benzyl-p-tolylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 25%. MS [M-CF₃COO]⁺: 469.

EXAMPLE 553-(R)(Benzylphenylcarbamoyloxy)-1-[2-2-methoxyethoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 390 mg, 84%. ¹H-NMR (DMSO-d₆): δ 1.55-1.75 (m, 2 H),1.88 (m, 2H), 2.17 (s, 1H), 3.14 (m, 1H), 3.22 (s, 3H), 3.29-3.55 (m,10H), 3.78 (m, 2H), 3.90 (m, 1H), 4.89 (s, 2H), 4.99 (m, 1H), 7.17-7.35(m, 10H); MS [M-Br]⁺: 439.

EXAMPLE 563-(R)(Benzylphenylcarbamoyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 200 mg, 65%. ¹H-NMR (DMSO-d₆): δ 1.55-1.75 (m, 2H),1.90 (m, 2H), 2.19 (s, 1H), 3.00 (m, 2H), 3.10 (m, 1H), 3.31-3.51 (m,6H), 3.90 (m, 1H), 4.91 (s, 2H), 5.04 (m, 1H), 7.18-7.37 (m, 15H). MS[M-Br]⁺: 441; mp 81° C.

EXAMPLE 573-(R)(Benzylphenylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 970 mg, 82%. ¹H-NMR (DMSO-d₆): δ 1.55-1.69 (m, 2H),1.85-2.04 (m, 4H), 2.18 (s, 1H), 2.83 (m, 2H), 3.01 (m, 1H), 3.20-3.44(m, 6H), 3.85 (m, 1 H), 4.92 (s, 2H), 5.00 (m, 1H), 6.94-7.00 (m, 2 H),7.19-7.40 (m, 11H). MS [M-Br]⁺: 461; mp 95° C.

EXAMPLE 583-(R)(Benzylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 880 mg, 79%. ¹ H-NMR (DMSO-d₆): δ 1.55-1.69 (m, 2H),1.85-2.00 (m, 4H), 2.18 (s, 1H), 2.59 (m, 2H), 3.04 (m, 1H), 3.23-3.44(m, 6H), 3.85 (m, 1H), 4.92 (s, 2H), 5.02 (m, 1H), 7.18-7.36 (m, 15H).); MS [M-Br]⁺: 455; mp 101° C.

EXAMPLE 593-(R)(Benzylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 360 mg, 67%. ¹H-NMR (DMSO-d₆): δ 1.5-1.73 (m, 2H),1.89 (m, 2H), 2.20 (s, 11H), 3.23 (m, 1H), 3.46-3.72 (m, 6H), 4.02 (m,1H), 4.43 (m, 2H), 4.92 (s, 2H), 5.03 (m, 1H), 7.01 (m, 3H), 7.17-7.38(m, 12H); MS [M-Br]⁺: 457; mp 117° C.

EXAMPLE 603-(R)(Benzylphenylcarbamoyloxy)-1-[3-(3-cyanophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 36%; MS [M-CF₃COO]⁺: 496.

EXAMPLE 613-(R)(Benzylphenylcarbamoyloxy)-1-[3-naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 21%; MS [M-CF₃COO]⁺: 521.

EXAMPLE 623-(R)(Benzylphenylcarbamoyloxy)-1-[3-(methylphenylamino)propyl]-1azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 28%; MS [M-CF₃COO]⁺: 484.

EXAMPLE 633-(R)(Benzylphenylcarbamoyloxy)-1(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 8 mg, 18%; ¹H-NMR (DMSO-d₆): δ 1.45-2.00 (m, 6H),2.17 (bs, 1H), 3.00 (m, 2H), 3.28-3.41 (m, 7H), 3.83 (m, 1H), 4.91 (s,2H), 4.98 (m, 1H), 7.18-7.41 (m, 15H); MS [M-CF₃COO]⁺: 487.

EXAMPLE 643-(R)(Benzylphenylcarbamoyloxy)-1-(4-oxo-4-phenylbutyl-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 23%; ¹H-NMR (DMSO-d₆): δ 1.50-2.06 (m, 6H),2.20 (bs, 1H), 3.13-3.47 (m, 9H), 3.89 (m, 1H), 4.93 (s, 2H), 5.02 (m,1H), 7.19-7.38 (m, 10H), 7.54-7.70 (m, 3H), 7.98-8.00 (m, 2H); MS[M-CF₃COO]⁺: 483.

EXAMPLE 653-(R)(Benzylphenylcarbamoyloxy)-1-[3-(2,4,6-trimethylphenoxy)propyl]-1azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 30%; ¹H-NMR (DMSO-d₆): δ 1.50-2.20 (m, 7H),2.19 (s, 9H), 3.16-3.52 (m, 7H), 3.73 (m, 2H), 3.92 (m, 1H), 4.93 (s,2H), 5.03 (m, 1H), 6.83 (s, 2H), 7.19-7.38 (m, 10H); MS (M-CF₃COO]⁺:513.

EXAMPLE 663-(R)(Benzylphenylcarbamoyloxy)-1-[3-(2-chlorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 31%; MS [M-CF₃COO]⁺: 506.

EXAMPLE 673-(R)(Benzylphenylcarbamoyloxy)-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 29%; ¹H-NMR (DMSO-d₆): δ 1.50-2.00 (m, 4H),2.08-2.20 (m, 3H), 3.12-3.50 (m, 7H), 3.90 (m, 1H), 4.14 (m, 2H), 4.93(s, 2H), 5.03 (m, 1H), 7.19-7.38 (m, 13H), 7.54-7.59 (m, 1H). MS[M-CF₃COO]⁺: 539.

EXAMPLE 683-(R)(Benzylphenylcarbamoyloxy)-1-[3-biphenyl-4-oxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 24%; ¹H-NMR (DMSO-d₆): δ 1.50-2.20 (m, 7H),3.14 (bs, 1H), 3.28-3.52 (m, 6 H), 3.91 (m, 1H), 4.10 (m, 2H), 4.93 (s,2H), 5.03 (m, 1H), 7.03-7,08 (m, 2H), 7.18-7.47 (m,13H), 7.61-7.65 (m,4H); MS [M-CF₃COO]⁺: 547.

EXAMPLE 693-(R)(Benzylphenylcarbamoyloxy)-1-[3-(2,4difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 22%; ¹H-NMR (DMSO-d₆): δ 1.5-2.19 (m, 7H),3.10 (bs, 1H), 3.28-3.51 (m,6H), 3.90 (m, 1H), 4.10 (m, 2H), 4.93 (s,2H), 5.02 (m, 1H), 7.02-7.09 (m, 1H), 7.19-7.37 (m, 12H); MS[M-CF₃COO]⁺: 507.

EXAMPLE 703-(R)(Benzylphenylcarbamoyloxy)-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 22%; ¹H-NMR (DMSO-d₆): 1.50-2.19 (m, 7H), 3.11(bs, 1H), 3.28-3.51 (m, 6H), 3.70 (s,3H), 3.89 (m, 1H), 3.94-3.99 (m,2H), 4.93 (s, 2H), 5.02 (m, 1H), 6.85-6.92 (m, 4H), 7.19-7.38 (m, 10H);MS [M-CF₃COO]⁺: 501.

EXAMPLE 713-(R)(Benzylphenylcarbamoyloxy)-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 21%; ¹H-NMR (DMSO-d₆): δ 1.50-1.71 (m, 6H),1.87-2.19 (m, 5H), 2.63-2.68 (m, 4H), 3.10 (bs, 1H), 3.28-3.50 (m, 6H),3.88 (m, 1H), 3.98 (m, 2H), 4.93 (s, 2H), 5.02 (m, 1H), 6.63-6.70 (m,2H), 6.95-6.98 (d, 1H), 7.19-7.38 (m, 10H); MS [M-CF₃COO]⁺: 525.

EXAMPLE 721-[3-Benzo[1,3]dioxol-5-yloxy)propyl]-3-(R)(benzylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 26%; MS [M-CF₃COO]⁺: 515.

EXAMPLE 733-(R)(Benzylphenylcarbamoyloxy)-1-[3-(2-carbamoylphenoxy)propyl]-1azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 22%; ¹H-NMR (DMSO-d₆): δ 1.50-2.27 (m, 7H),3.09 (bs, 1H), 3.28-3.48 (m, 6H), 3.88 (m, 1H), 4.14 (m, 2H), 4.93 (s,2H), 5.04 (m, 1H),7.02-7.15 (m, 2H), 7.19-7.38 (m, 10H), 7.44-7.50 (m,1H), 7.55(bs, NH₂), 7.69-7.72 (dd,1H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 743-(R)(Benzylphenylcarbamoyloxy)-1-[3-(3-dimethylaminophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 26%; MS [M-CF₃COO]⁺: 514.

EXAMPLE 751-[3-(4-Acetylaminophenoxy)propyl]-3-(R)(benzylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 25%; ¹H-NMR (DMSO-d₆): δ 1.50-1.92 (m, 4H),2.01 (s, 3H), 2.04-2.20 (m, 3H), 3.12 (bs, 1H), 3.28-3.51 (m, 6H), 3.89(m, 1H), 4.00 (m, 2H), 4.93 (s, 2H), 5.02 (m, 1H), 6.86-6.91 (m, 2H),7.19-7.38 (m, 10H), 7.48-7.53 (m, 2H), 9.85 (s,NH); MS [M-CF₃COO]⁺: 528.

EXAMPLE 763-(R)(Benzylphenylcarbamoyloxy)-1-[3-(4-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 25%; ¹H-NMR (DMSO-d₆): δ 1.50-2.20 (m, 7H),3.12 (bs, 1H), 3.29-3.51 (m, 6H), 3.82 (s, 3H), 3.87-3.93 (m, 1H), 4.14(m, 2H), 4.93 (s, 2H), 5.03(m, 1H), 7.04-7.09 (m, 2H), 7.19-7.38 (m,10H), 7.92-7.96 (m, 2H);. MS [M-CF₃COO]⁺: 529.

EXAMPLE 773-(R)(Benzylphenylcarbamoyloxy)-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 26%; ¹H-NMR (DMSO-d₆): δ 1.50-2.27 (m, 7H),3.12 (bs, 1H), 3.29-3.51 (m, 6H), 3.87-3.94 (m, 1H), 4.21 (m, 2H), 4.93(s, 2H), 5.03 (m, 1H), 7.14-7.38 (m, 12H), 8.22-8.28 (m, 2H); MS[M-CF₃COO]⁺: 516.

EXAMPLE 783-(R)(Benzylphenylcarbamoyloxy)-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 22%; MS [M-CF₃COO]⁺: 501.

EXAMPLE 79 Benzylphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(S)ylester

The title compound was synthesised according to method a. The yield ofthe final step was 1000 mg, 23%; ¹H-NMR (DMSO-₆): δ 1.14-1.57 (m, 4H),1.83 (bs, 1H), 2.43-2.61 (m, 5H), 2.61-3.01 (m, 1H), 4.64 (m, 1H), 4.89(s, 2H), 7.16-7.35 (m, 10H). MS [M+1]⁺: 337.

EXAMPLE 803-(S)(Benzylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 660 mg, 83%. ¹H-NMR (DMSO-d₆) δ 1.40-2.00 (m, 6H),2.18 (bs, 1H), 2.59 (m, 2H), 2.95-3.44 (m, 7H), 3.84 (m, 1H), 4.92 (s,2H), 5.00 (m, 1H), 7.19-7.36 (m, 15H). MS [M-Br]⁺: 455; mp: 64° C.

EXAMPLE 813-(R)(Butylphenylcarbamoyloxy)-1-methyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 30%; MS [M-CF₃COO]⁺: 317.

EXAMPLE 823-(R)(Butylphenylcarbamoyloxy)-1-(4-methylpent-3-enyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 18 mg, 27%; MS [M-CF₃COO]⁺: 385.

EXAMPLE 833-(R)(Butylphenylcarbamoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 21 mg, 28%; MS [M-CF₃COO]⁺: 437.

EXAMPLE 843-(R)(Butylphenylcarbamoyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 182 mg, 48%; ¹H-NMR (PMSO-d₆): δ 0.84 (m, 3H), 1.25(m, 2H), 1.40 (m, 2H), 1.70-1.91 (m, 4H), 2.20 (s, 1H), 3.2-3.4 (m, 6H), 3.64 (m, 2H), 3.88 (m, 1H), 3.88-4.07 (d, 2H), 4.97 (m, 1H), 6.45(m, 1H), 6.83-6.88 (d, 1H), 7.23-7.45 (m, 7H), 7.60 (m, 2H); MS [M-Br]⁺:419; mp: 144° C.

EXAMPLE 851-Allyl-3-(R)(butylphenylcarbamoyloxy)-1--azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 200 mg, 72%; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 3H),1.21-1.34 (m, 3H), 1.40-1.45 (m, 2H), 1.70-2.18 (m, 4H), 3.15-3.40(m,5H), 3.61-3.67 (m, 2H), 3.82 (m, 1H), 3.92-3.94 (m, 2H), 4.95 (m,1H), 5.62 (m, 2H), 5.97-6.01 (m, 1H), 7.26-7.44 (m, 5H); MS [M-Br]⁺:343; mp: 141° C.

EXAMPLE 863-(R)(Butylphenylcarbamoyloxy)-1-(2-hydroxyethyl)-1azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 19%; MS [M-CF₃COO]⁺: 347.

EXAMPLE 873-(R)(Butylphenylcarbamoyloxy)-1-isopropyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 20 mg, 29%; MS [M-CF₃COO]⁺: 345.

EXAMPLE 883-(R)(Butylphenylcarbamoyloxy)-1-propyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 23%; MS [M-CF₃COO]⁺: 345.

EXAMPLE 893-(R)(Butylphenylcarbamoyloxy)-1-(3-cyanopropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 20%; MS [M-CF₃COO]⁺: 370.

EXAMPLE 903-(R)(Butylphenylcarbamoyloxy)-1-cyclopropylmethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 2 mg, 3%; MS [M-CF₃COO]⁺: 357.

EXAMPLE 913-(R)(Butylphenylcarbamoyloxy)-1-(2-ethoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 19 mg, 25%; MS [M-CF₃COO]⁺: 375.

EXAMPLE 923-(R)(Butylphenylcarbamoyloxy)-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 14%; MS [M-CF₃COO]⁺: 431.

EXAMPLE 933-(R)(Butylphenylcarbamoyloxy)-1-(3-hydroxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 17%; MS [M-CF₃COO]⁺: 361.

EXAMPLE 943-(R)(Butylphenylcarbamoyloxy)-1-(3-pyrrol-1-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 19 mg, 23%; MS [M-CF₃COO]⁺: 410.

EXAMPLE 951-(4-Acetoxybutyl)-3-(R)(butylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 12%; MS [M-CF₃COO]⁺: 417.

EXAMPLE 963-(R)(Butylphenylcarbamoyloxy)-1-(4-oxo-4-thiophen-2-ylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 17 mg, 19%; MS [M-CF₃COO]⁺: 455.

EXAMPLE 973-(R)(Butylphenylcarbamoyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 17 mg, 20%; MS [M-CF₃COO]⁺: 435.

EXAMPLE 983-(R)(Butylphenylcarbamoyloxy)-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 21 mg, 23%; MS [M-CF₃COO]⁺: 453.

EXAMPLE 993-(R)(Butylphenylcarbamoyloxy)-1-heptyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 17 mg, 21%; MS [M-CF₃COO]⁺: 401.

EXAMPLE 1001-(2-Benzyloxyethyl)-3-(R)(butylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 22 mg, 25%; MS [M-CF₃COO]⁺: 437.

EXAMPLE 1013-(R)(Butylphenylcarbamoyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 330 mg 82%; ¹H-NMR (DMSO-d₆): δ 0.83 (m, 3H),1.27-1.34 (m, 2H), 1.41-1.48 (m, 3H), 1.60-2.23 (m, 4H), 2.96-3.47 (m,7H), 3.57-3.71 (m, 4H), 3.92 (m, 1H), 4.98 (m, 1H), 7.25-7.45 (m, 10H);MS [M-Br]⁺: 407; mp: 139° C.

EXAMPLE 1023-(R)(Butylphenylcarbamoyloxy)-1-[2-(2-methoxyethoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 520 mg, 81%; ¹H-NMR (DMSO-d₆): δ 0.82 (m, 3H),1.24-1.31 (m, 2H), 1.39-1.47 (m, 2H), 1.70-2.20 (m, 5 H), 3.26 (s, 3H),3.35-3.70 (m, 13H), 3.82-3.86 (m, 3H), 4.94 (m, 1H), 7.26-7.44 (m, 5 H);MS [M-Br]⁺: 405.

EXAMPLE 103 Butyl-(4-fluorophenyl)carbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 1650 mg, 24%; ¹H-NMR (DMSO-d₆): δ 0.82 (m, 3H),1.20-1.54 (m, 8H), 1.83 (m, 1H), 2.49-2.70) (m, 5H), 3.02-3.09 (m, 1H),3.36-3.63 (m, 2H), 4.59 (m, 1H), 7.19-7.35 (m, 4H); MS [M+1]⁺: 321.

EXAMPLE 1043-(R)(Butylphenylcarbamoyloxy)-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;chloride

The title compound was synthesised according to method c. The yield ofthe final step was 390 mg, 75%; ¹H-NMR (DMSO-d₆): δ 0.82 (m, 3H),1.26-1.31 (m, 2H), 1.40-1.48 (m, 2H), 1.70-2.17 (m,5H), 3.20-3.7 (m,11H), 3.86 (m, 1H), 4.02 (m, 2H), 4.94 (m, 1H), 6.95-7.00 (m, 2H),7.12-7.18 (m, 2H), 7.26-7.44 (m, 5H); MS [M-Cl]⁺: 455; mp: 126° C.

EXAMPLE 1053-(R)(Butylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 260 mg, 53%; ¹H-NMR (DMSO-d₆): δ 0.84 (m, 3H),1.23-1.30 (m, 2H), 1.39-1.48 (m, 2H), 1.70-2.20 (m, 5H), 3.20-3.72 (m,9H), 3.99 (m, 1H), 4.44 (m, 2H), 4.95 (m, 1H), 7.01 (m, 3H), 7.24-7.40(m, 7H); MS [M-Br]⁺: 423; mp: 153° C.

EXAMPLE 1063-(R)(Butylphenylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 1100 mg, 62%; ¹H-NMR (DMSO-d₆): δ 0.84 (m, 3H),1.24-1.31 (m, 2H), 1.42 (m, 2H), 1.60-2.21 (m, 7H), 2.85 (m, 2H),3.0-3.50 (m, 7H), 3.60-3.69 (m, 2H), 3.85 (m, 1H), 4.93 (m, 1H),6.95-7.00 (m, 2H), 7.28-7.43 (m, 6H); MS [M-Br]⁺: 427; mp: 127° C.

EXAMPLE 1073-(R)(Butylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 280 mg, 56%; ¹H-NMR (DMSO-d₆): δ 0.84 (m, 3H),1.23-1.33 (m, 2H), 1.43 (m, 2H), 1.60-2.20 (m, 7H), 2.59 (m, 2H),3.00-3.78 (m, 9H), 3.84 (m, 1H), 4.92 (m, 1H), 7.20-7.42 (m, 10H); MS[M-Br]⁺: 421; mp: 120° C.

EXAMPLE 108 Phenylthiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 310 mg, 10%; ¹H-NMR (DMSO-d₆): δ 1.10-1.60 (m, 4 H),1.87 (s, 1H), 2.46-2.63 (m, 5H), 3.04-3.33 (m, 1H), 4.66 (m, 1H), 5.01(s, 2H), 6.87-6.94 (m, 2H), 7.20-7.43 (m, 6H); MS [M+1]⁺: 343.

EXAMPLE 1091-Methyl-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 160 mg, 80%; ¹H-NMR (DMSO-d₆): 1.65-2.00 (m, 4H),2.20 (s, 1 H), 2.98 (s, 3H), 3.32-3.52 (m, 5H), 3.85-3.92 (m, 1H),4.98-5.04 (m, 3H), 6.94 (m, 2H), 7.24-7.45 (m, 6H); MS [M-Br]⁺: 357.

EXAMPLE 1101-(3-Phenoxypropyl)-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised-according to method d. The yield ofthe final step was 16 mg, 42%; MS [M-CF₃COO]⁺: 477.

EXAMPLE 1111-(3-Phenylpropyl)-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 35%; ¹H-NMR (DMSO-d₆): δ 1.72-2.3 (m, 7H),2.58 (m, 2H), 3.00-3.48 (m, 7H), 3.84 (m, 1H), 5.04 (m, 3H), 6.92-6.94(m, 2H), 7.20-7.43 (m, 11H); MS [M-CF₃COO]⁺: 461.

EXAMPLE 1121-(3-Phenylallyl)-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 4 mg, 11%; MS [M-CF₃COO]⁺: 459.

EXAMPLE 1131-(2-Benzyloxyethyl)-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 37%; MS [M-CF₃COO]⁺: 477.

EXAMPLE 1141-[3-(3-Hydroxyphenoxy)propyl]-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 11 mg, 28%, MS [M-CF₃COO]⁺: 493.

EXAMPLE 1151-Heptyl-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 37%; MS [M-CF₃COO]⁺: 441.

EXAMPLE 1163-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 140 mg, 48%; ¹H-NMR (DMSO-d₆): δ 1.40-2.30 (m, 7H),2.83 (m, 2H), 3.00-3.60 (m, 7H), 3.88 (m, 1H), 5.04 (m, 3H), 6.93-6.99(m, 4H), 7.28-7.43 (m, 7H); MS [M-Br]⁺: 467.

EXAMPLE 1171-(2-Phenoxyethyl)-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 510 mg, 80%; ¹H-NMR (DMSO-d₆): δ 1.40-2.30 (m, 5H),3.20-3.73 (m, 7H), 4.05 (m, 1H), 4.44 (bs, 2H), 5.04 (m, 3H), 6.91-7.04(m, 5H), 7.24-7.41 (m, 8H); MS [M-Br]⁺: 463; mp: 133° C.

EXAMPLE 1181-Allyl-3-(R)(phenylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 360 mg, 66%; ¹H-NMR (DMSO-d₆): δ 1.40-2.30 (m, 5H),3.00-3.41 (m, 5H), 3.81-3.92 (m, 3H), 5.04 (m, 3H), 5.61 (m, 2H),5.93-6.05 (m, 1H), 6.93-6.96 (m, 2H), 7.24-7.46 (m, 6H); MS [M-Br]⁺:383; mp: 110° C.

EXAMPLE 119 Phenethylphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)ylester

The title compound was synthesised according to method a. The yield ofthe final step was 1400 mg, 17%; ¹H-NMR (DMSO-d₆): δ 1.10-1.60 (m, 4H),1.83 (s, 1H), 2.40-2.70 (m, 5H), 2.78 (m, 2H), 3.00-3.08 (m, 1H), 3.87(m, 2H), 4.58 (m, 1H), 7.16-7.40 (m, 10H); MS [M+1]⁺: 351.

EXAMPLE 1201-Methyl-3-(R)(phenethylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was-synthesised according to method c. The yield ofthe final step was 140 mg, 73%; ¹H-NMR (DMSO-d₆): δ 1.40-2.30 (m, 5H),2.80 (m, 2H), 2.94 (s, 3H), 3.10-3.50 (m, 5H), 3.78-3.95 (m, 3H), 4.89(m, 1H), 7.16-7.41 (m, 10H); MS [M-Br]⁺: 365; mp: 203° C.

EXAMPLE 1211-Allyl-3-(R)(phenethylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 11 mg, 35%; MS [M-CF₃COO]⁺: 391.

EXAMPLE 1223-(R)(Phenethylphenylcarbamoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 41%; MS [M-CF₃COO]⁺: 485.

EXAMPLE 1233-(R)(Phenethylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 40%; ¹H-NMR (DMSO-d₆): δ 1.45-2.18 (m, 5H),2.81 (m, 2H), 3.28-3.70 (m, 7H), 3.80-4.02 (m, 3H), 4.43 (m, 2H), 4.95(m, 1H), 6.98-7.04 (m, 2H), 7.16-7.40 m, 13H); MS [M-CF₃COO]⁺: 471.

EXAMPLE 1243-(R)(Phenethylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 37%; ¹H-NMR (DMSO-d₆): δ 1.45-2.20 (m, 7H),2.59 (m, 2H), 2.81 (m, 2H), 3.05-3.5 (m, 7H), 3.78-3.89 (m, 3H), 4.91(m, 1H), 7.17-7.42 (m, 15H); MS [M-CF₃COO]⁺: 469.

EXAMPLE 1253-(R)(Phenethylphenylcarbamoyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 4 mg, 11%; MS [M-CF₃COO]⁺: 467.

EXAMPLE 1261-(2-Benzyloxyethyl)-3-(R)(phenethylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 36%; MS [M-CF₃COO]⁺: 485.

EXAMPLE 1271-[3-(3-Hydroxyphenoxy)propyl]-3-(R)(phenethylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 35%; ¹H-NMR (DMSO-d₆): δ 1.45-2.20 (m, 7H),2.82 (m, 2H), 3.05-3.50 (m, 7H), 3.83-3.99 (m, 5H), 4.94 (m, 1H),6.33-6.39 (m, 3H), 7.04-7.09 (m, 1H), 7.18-7.44(m, 10H), 9.49 (s, OH);MS [M-CF₃COO]⁺: 501.

EXAMPLE 1281-Heptyl-3-(R)(phenethylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 42%; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 3H), 1.28(m, 8H), 1.55-2.20 (m, 7H), 2.82 (m, 2H), 3.00-3.50 (m, 7H), 3.68-3.89(m, 3H), 4.92 (m, 1H), 7.18-7.43 (m, 10H); MS [M-CF₃COO]⁺: 449.

EXAMPLE 1293-(R)(Phenethylphenylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 39%; MS [M-CF₃COO]⁺: 475.

EXAMPLE 130 Pentylphenylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)ylester

The title compound was synthesised according to method a. The yield ofthe final step was 62.0 mg, 9%; ¹H-NMR (DMSO-d₆): δ 0.83 (m, 3H),1.22-1.30 (m, 5H), 1.43-1.56 (m, 5H), 1.83 (s, 1H), 2.42-2.65 (m, 5H),3.01-3.06 (m, 1 H), 3.59-3.65 (m, 2H), 4.49 (m, 1H), 7.22-7.41 (m, 5 H);MS [M+1]⁺: 317.

EXAMPLE 1311-Methyl-3-(R)(pentylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 130 mg, 68%, ¹H-NMR (DMSO-d₆): δ 0.81 (m, 3H), 1.21(m, 5H), 1.45-2.20 (m, 6H), 2.93 (s, 3H), 3.10-3.70 (m, 7H), 3.80 (m,1H), 4.88 (m, 1H), 7.24-7.41 (m, 5H); MS [M-Br]⁺: 331.

EXAMPLE 1321-Allyl-3-(R)(pentylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 35%; ¹H-NMR (DMSO-d₆): δ 0.83 (m, 3H),1.21-1.28 (m, 4H), 1.46 (m, 3H), 1.54-1.91 (m, 3H), 2.30 (m, 1H),3.28-3.41 (m, 5H), 3.78-3.92 (m, 5H), 4.94 (m, 1H), 5.54-5.64 (m, 2H),5.98 (m, 1H), 7.26-7.43 (m, 5H); MS [M-CF₃COO]⁺: 357.

EXAMPLE 1333-(R)(Pentylphenylcarbamoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 36%; MS [M-CF₃COO]⁺: 451.

EXAMPLE 1343-(R)(Pentylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 14 mg, 40%; ¹H-NMR (DMSO-d₆): δ 0.82 (m, 3H), 1.23(m, 4H), 1.46 (m, 3H), 1.54-1.91 (m, 3H), 2.25 (s, 1H), 3.28-3.70 (m,9H), 3.98 (m, 1H), 4.43 (m, 2H), 4.95 (m, 1H), 6.98-7.04 (m, 3H),7.23-7.4 (m, 7H); MS [M-CF₃COO]⁺: 437.

EXAMPLE 1353-(R)(Pentylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 37%; ¹H-NMR (DMSO-d₆): δ 0.82 (m, 3H),1.20-1.25 (m, 5H), 1.44 (m, 3H), 1.68-2.13 (m, 7H), 2.58 (m, 2H),3.00-3.41 (m, 5H), 3.54-3.69 (m, 2H), 3.79-3.85 (m, 1H), 4.92 (m, 1H),7.20-7.42 (m, 10H); MS [M-CF₃COO]⁺: 435.

EXAMPLE 1363-(R)(Pentylphenylcarbamoyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 4 mg, 12%; MS [M-CF₃COO]⁺: 433.

EXAMPLE 1371-(2-Benzyloxyethyl)-3-(R)(pentylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 42%; MS [M-CF₃COO]⁺: 451.

EXAMPLE 1381-[3-(3-Hydroxyphenoxy)propyl]-3-(R)(pentylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg 32%; MS [M-CF₃COO]⁺: 467.

EXAMPLE 1391-Heptyl-3-(R)(pentylphenylcarbamoyloxy)-1-azoniabicyclo]2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 45%; MS [M-CF₃COO]⁺: 415.

EXAMPLE 1403-(R)(Pentylphenylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 37%; ¹H-NMR (DMSO-d₆): δ 0.82 (m, 3H),1.22-1.26 (m, 5H), 1.46 (m, 3H), 1.60-2.14 (m, 7H), 2.82 (m,2H),3.20-3.41 (m, 5H), 3.50-3.70 (m, 2H), 3.82 (m, 1H), 4.92 (m, 1H),6.93-6.99 (m, 2 H), 7.25-7.43 (m, 6H); MS M CF₃COO]⁺: 441.

EXAMPLE 141 Pent-4-enylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a The yield ofthe final step was 690 mg, 14%; ¹H-NMR (DMSO-d₆): δ 1.10-1.60 (m, 6 H),1.84 (bs, 1H), 1.97-2.04 (m, 2H), 2.45-2.65 (m, 5H), 3.02-3.10 (m, 1H),3.29-3.66 (m, 2H), 4.59 (m, 1H), 4.61-5.00 (m, 2H), 5.70-5.84 (m, 1H),7.22-7.42 (m, 5H); MS [M+1]⁻: 315.

EXAMPLE 1421-Allyl-3-(R)(pent-4-enylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 35%; MS [M-CF₃COO]⁺: 355.

EXAMPLE 1433-(R)(Pent-4-enylphenylcarbamoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 42%; ¹H-NMR (DMSO-d₆): δ 1.50-2.20 (m, 11H),3.23-3.47 (m, 7H), 3.56-3.73 (m, 2H), 3.87 (m, 1H), 4.03 (m, 2H),4.92-4.95 (m, 2H), 5.00 (m, 1H), 5.70-5.82 (m, 1H), 6.93-6.99 (m, 2H),7.26-7.44 (m, 8H); MS [M-CF₃COO]⁺: 449.

EXAMPLE 1443-(R)(Pent-4-enylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 37%; ¹H-NMR (DMSO-d₆): δ 1.55 (m, 2H),1.65-2.20 (m, 7H), 3.28-3.75 (m, 9H), 3.98 (m, 1H), 4.43 (bs, 2H),4.92-4.99 (m, 3H), 5.70-5.83 (m, 1H), 6.98-7.04 (m, 3H), 7.24-7.40 (m,7H); MS [M-CF₃COO]⁺; 435.

EXAMPLE 1463-(R)(Pent-4-enylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 37%; ¹H-NMR (DMSO-d₆): δ 1.56 (m, 3H),1.70-2.14 (m, 8H), 2.58 (m, 2H), 3.19-3.41 (m, 7H), 3.56-3.71 (m, 2H),3.81 (m, 1H), 4.92-4.99 (m, 3H), 5.70-5.83 (m 1H), 7.20-7.43 (m, 10H);MS [M-CF₃COO]⁺: 433.

EXAMPLE 1463-(R)(Pent-4-enylphenylcarbamoyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 4 mg, 12%; MS [M-CF₃COO]⁺: 431.

EXAMPLE 1471-(2-Benzyloxyethyl)-3-(R)(pent-4-enylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 44%; MS [M-CF₃COO]⁺: 449.

EXAMPLE 1481-[3-(3-Hydroxyphenoxy)propyl]-3-(R)(pent-4-enylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 32%; MS [M-CF₃COO]⁺: 465.

EXAMPLE 1491-Heptyl-3-(R)(pent-4-enylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 3 mg, 9%; MS [M-CF₃COO]⁺: 413.

EXAMPLE 1501-Methyl-3-(R)(pent-4-enylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 49%; MS [M-CF₃COO]⁺: 429.

EXAMPLE 1513-(R)(Pent-4-enylphenylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 43%; ¹H-NMR (DMSO-d₆): δ 1.40-2.20 (m, 11H),2.82 (m,2H), 3.05-3.5 (m, 7H), 3.58-3.86 (m, 3H), 4.92-4.95 (m, 2H) 5.00(m, 1H), 5.70-5.84 (m, 1H), 6.93-7.00 (m, 2H), 7.26-7.44 (m, 6H); MS[M-CF₃COO]⁺: 439.

EXAMPLE 152 Phenylthiophen-3-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 2000 mg, 15%; ¹H-NMR (DMSO-d₆): δ 1.10-1.60 (m, 4H),1.84 (bs, 1H), 2.46-2.62 (m, 5H), 3.02-3.10 (m, 1H), 4.62-4.67 (m, 1H),4.84 (s, 2H), 6.99 (m, 1H), 7.18-7.36 (m, 6H), 7.47-7.50 (m, 1H); MS[M+1]⁺: 343.

EXAMPLE 1531-Allyl-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 8 mg, 26%; ¹H-NMR (DMSO-d₆): δ 1.45-2.00 (m, 4H),2.21 (bs, 1H), 3.04-3.42 (m, 5H), 3.78-3.91 (m, 3H), 4.87 (s, 2H), 5.02(m, 1H), 5.54-5.64 (m, 2H), 5.91-6.02 (m, 1H), 7.00-7.02 (m, 1H),7.22-7.39 (m, 6H), 7.50-7.52 (m, 1H); MS [M-CF₃COO]⁺: 383.

EXAMPLE 1541-(3-Phenoxypropyl)-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 31%; MS [M-CF₃COO]⁺: 477.

EXAMPLE 1551-(3-Phenylpropyl)-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 15 mg, 41%; ¹H-NMR (DMSO-d₆): δ 1.45-2.18 (m, 7H),2.59 (m, 2H), 3.02-3.44 (m, 7H), 3.84 (m, 1H), 4.87 (s, 2H), 4.99 (m,1H), 7.00 (m, 1H), 7.21-7.38 (m, 11H), 7.47-7.50 (m, 1H); MS[M-CF₃COO]⁺: 461.

EXAMPLE 1561-(3-Phenylallyl)-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 4 mg, 11%; MS [M-CF₃COO]⁺: 459.

EXAMPLE 1571-(2-Benzyloxyethyl)-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 16 mg, 42%; MS [M-CF₃COO]⁺: 477.

EXAMPLE 1581-[3-(3-Hydroxyphenoxy)propyl]-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 33%; MS [M-CF₃COO]⁺: 493.

EXAMPLE 1591-Methyl-3-(R)(phenylthiophen-3-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 12 mg, 42%; MS [M-CF₃COO]⁺: 357.

EXAMPLE 1603-(R)(Phenylthiophen-3-ylmethylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 500 mg, 78%; ¹H-NMR (DMSO-d₆): δ 1.45-2.19 (m, 7H),2.83 (m, 2H), 3.04-3.13 (m, 1H), 3.19-3.46 (m, 6H), 3.83-3.90 (m, 1H).4.88 (s, 2H), 4.99 (m, 1H), 6.94 (m, 3H), 7.20-7.40 (m, 7H), 7.49 (m,1H); MS [M-Br]⁺: 467; mp: 110° C.

EXAMPLE 1613-(R)(Phenylthiophen-3-ylmethylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 350 mg, 63%; ¹H-NMR (DMSO-d₆): δ 1.45-2.20 (m, 5H),3.27 (m, 1H), 3.40-3.80 (m, 6H), 4.00-4.06 (m, 1H), 4.44 (bs, 2H), 4.87(s, 2H), 5.02 (m, 1H), 6.99-7.04 (m, 4H), 7.20-7.38 (m, 8H), 7.48 (m,1H); MS [M-Br]⁺: 463; mp: 131° C.

EXAMPLE 162 Butylthiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 1300 mg, 29%; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 3H),1.19-1.68 (m, 8H), 1.92 (m,1H), 2.49-2.64 (m, 5H), 3.05-3.22 (m, 3H),4.56-4.62 (m, 3H), 6.95-7.04 (m, 2H), 7.42-7.44 (m, 1H); MS [M+1]⁺: 323.

EXAMPLE 1631-Allyl-3-(R)(butylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 23%; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 3H),1.20-1.26 (m, 2H), 1.42-1.49 (m, 2H), 1.58-2.05 (m, 4H), 2.32 (bs, 1H),3.20-3.41 (m, 7H), 3.74-3.94 (m, 3H), 4.51-4.72 (m, 2H), 4.99 (m, 1H),5.55-5.64 (m, 2H), 5.87-6.10 (m, 1H), 6.99 (m, 1H), 7.08 (m, 1H), 7.46(m, 1H); MS [M-CF₃COO]⁺: 363.

EXAMPLE 1643-(R)(Butylthiophen-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 25%; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 3H),1.19-1.26 (m, 2H),1.41-1.50 (m, 2H), 1.75-2.10 (m, 6H), 2.30 (bs, 1H),2.59 (m, 2H), 3.10-3.50 (m, 9H), 3.83 (m, 1 H), 4.50-4.74 (m, 2H),4.97(m, 1H), 6.97 (m, 1H), 7.07 (m, 1H), 7.20-7.35 (m, 5H), 7.43 (m, 1H); MS[M-CF₃COO]⁺: 441.

EXAMPLE 165 bis-Thiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 340 mg, 7%; ¹H-NMR (DMSO-d₆): δ 1.28-1.31 (m, 1H),1.45-1.72 (m, 3H), 1.94-1.97 (m, 1H), 2.49-2.71 (m, 5H), 3.06-3.14 (m,1H), 4.50-4.57 (m, 4H),4.62-4.69 (m, 1H), 6.96-7.06 (m, 4H), 7.44-7.46(m, 2H); MS [M+1]⁺: 363.

EXAMPLE 1661-Allyl-3-(R)(bis-thiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 9 mg, 19%; ¹H-NMR (DMSO-d₆): δ 1.70-2.06 (m, 4H),2.35 (bs, 1H), 3.25-3.50 (m, 5H), 3.80-3.94 (m, 3H), 4.54-4.71 (m, 4H),5.10 (m, 1H), 5.55-5.65 (m, 2H), 5.87-6.10 (m, 1H), 6.98-7.01 (m, 2H);7.06-7.10 (m, 2H), 7.47-7.48 (m, 2H); MS [M-CF₃COO]⁺: 403.

EXAMPLE 1673-(R)(bis-thiophen-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to method c. The yield ofthe final step was 690 mg, 82%; ¹H-NMR (DMSO-d₆): δ 1.78-2.10 (m, 6H),2.34 (bs, 1H), 2.53-2.63 (m, 2H), 3.23-3.48 (m, 7H), 3.88 (m, 1H),4.53-4.74 (m, 4H), 5.05 (m, 1H), 6.98-7.01 (m, 2H), 7.02-7.11 (m, 2H),7.21-7.37 (m, 5H), 7.44-7.48 (m, 2H); MS [M-Br]⁺: 481.

EXAMPLE 168 Furan-2-ylmethyl-2-thiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 700 mg, 10%; ¹H-NMR (DMSO-d₆): δ 1.10-1.34 (m, 1H),1.44-1.67 (m, 3H), 1.93 (bs, 1H), 2.50-2.70 (m, 5H), 3.05-3.12 (m, 1H),3.37-4.40 (m, 2H), 4.57-4.66 (m, 3H), 6.26-6.42 (m, 2H), 6.95-7.03 (m,2H), 7.45 (m, 1H), 7.61 (m, 1H); MS [M+1]⁺: 347.

EXAMPLE 1691-Allyl-3-(R)(furan-2-ylmethylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 7 mg, 15%; MS [M-CF₃COO]⁺: 387.

EXAMPLE 1703-(R)(Furan-2-ylmethylthiophen-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 11 mg, 20%; ¹H-NMR (DMSO-d₆): δ 1.70-2.10 (m, 6H),2.31 (bs, 1H), 2.59 (m, 2H), 3.15-3.50 (m, 7H), 3.84 (m, 1H), 4.36-4.56(m, 4H), 5.03 (m, 1H), 6.32-6.44 (m, 2H), 6.92-7.08 (m, 2H), 7.20-7.35(m, 5H), 7.41-7.46 (m, 1H), 7.59-7.62 m, 1H); MS [M-CF₃COO]⁺: 465.

EXAMPLE 171 Allylthiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 3220 mg, 30%; ¹H-NMR (DMSO-d₆): δ 1.20-1.33 (m, 1H),1.45-1.80 (m, 3H), 1.93 (bs, 1H), 2.49-2.72 (m, 5H), 3.05-3.09 (m, 1H),3.81-3.83 (m, 2H), 3.83-4.55 (m, 3H), 5.14 (m, 2H), 5.70-5.82 (m, 1H),6.96-7.04 (m, 2H), 7.44-7.45 (m, 1H); MS [M+1]⁺: 307.

EXAMPLE 1721-Allyl-3-(R)(allylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 24%; ¹H-NMR (DMSO-d₆): δ 1.80-2.10 (m, 4H),2.32 (bs, 1H), 3.20-3.50 (m, 5H), 3.75-3.94 (m, 5H), 4.5-4.69 (m, 2H),5.01 (m, 1H), 5.10-5.23 (m, 2H), 5.51-5.65 (m, 2H), 5.70-5.85 (m, 1H),5.90-6.08 (m, 1H), 6.95-7.10 (m, 2H), 7.47 (m, 1H); MS [M-CF₃COO]⁺: 347.

EXAMPLE 1733-(R)(Allylthiophen-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 11 mg, 22%; ¹H-NMR (DMSO-d₆): δ 1.74-2.10 m, 6H),2.31 (bs, 1H), 2.59 (m, 2H), 3.16-3.56 (m, 7H), 3.76-3.90 (m, 3H),4.48-4.71 (m, 2H), 4.99 (m, 1H), 5.11-5.23 (m, 2H), 5.72-5.83 (m, 1H),6.98 (m, 1H), 7.06-7.07(m, 1H), 7.20-7.35 (m, 5H), 7.44 (m, 1H); MS[M-CF₃COO]⁺: 425.

EXAMPLE 1741-Allyl-3-(R)(cyclopentylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 10 mg, 22%; ¹H-NMR (DMSO d): δ 1.40-2.05 (m, 12H),2.27 (bs, 1H), 3.03,3.42 (m, 5H),3.70-3.95 (m, 3H), 4.15-4.35 (m, 1H),5.58 (m, 2H), 4.99 (m, 1H),5.54-5.65 (m, 2H), 5.87-6.10 (m, 1H), 6.97(m, 1H), 7.03 (m, 1H), 7.41-7.43 (m, 1H); MS [M-CF₃COO]⁺: 375.

EXAMPLE 1753-(R)(Cyclopentylthiophen-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 13 mg, 24%; ¹H-NMR (DMSO-d₆): δ 1.40-2.10 (m, 14H),2.25 (bs, 1H), 2.58 (m, 2H), 2.95-3.50 (m, 7H), 3.81 (m, 1H), 4.26 (m,1H), 4.50-4.70 (m, 2H), 4.97 (m, 1H), 6.93 (m, 1H), 7.03 (m, 1H),7.20-7.40 (m, 6H); MS [M-CF₃COO]⁺: 453.

EXAMPLE 176 Furan-2-ylmethylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 1400 mg, 18%; ¹H-NMR (DMSO-d₆): δ 1.19-1.60 (m, 4H),1.84 (bs, 1H), 2.44-2.57 (m, 5H), 3.01-3.09 (m, 1H), 4.63 (m, 1H), 4.82(s, 2H), 6.21 (m, 1H), 6,36 (m, 1H), 7.20-7.37 (m, 5H), 7.59 (m, 1H); MS[M+1]⁺; 327.

EXAMPLE 1771-Allyl-3-(R)(furan-2-ylmethylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 7 mg, 16%; ¹H-NMR (DMSO-d₆): δ; MS [M-CF₃COO]⁺: 367.

EXAMPLE 1783-(R)(Furan-2-ylmethylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 11 mg, 21%; ¹H-NMR (DMSO-d₆): δ 1.65-2.10 (m, 6H),2.19 (bs, 1H), 2.59 (m, 2H), 3.10-3.50 (m, 7H), 3.83 (m, 1H), 4.85 (bs,2H), 4.98 (m, 1H), 6.26 (m, 1H), 6.36 (m, 1H), 7.20-7.39 (m, 10H), 7.59(m, 1H); MS [M-CF₃COO]⁺: 445.

EXAMPLE 179 bis-Furan-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-(R)yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 2100 mg, 22%; ¹H-NMR (DMSO-d₆): δ 1.20-1.70 (m, 4H),1.89 (bs, 1H), 2.45-2.71 (m, 5H), 3.00-3.12 (m, 1H), 4.40 (m, 4H), 4.62(m, 1H), 6.22-6.40 (m, 4H), 7.59 (m, 2H); MS [M+1]⁺: 331.

EXAMPLE 1801-Allyl-3-(R)(bis-furan-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 7 mg, 16%; ¹H-NMR (DMSO-d₆): δ; MS [M-CF₃COO]⁺: 371.

EXAMPLE 1813-(R)(bis-furan-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to method d. The yield ofthe final step was 11 mg; 20%; ¹H-NMR (DMSO-d₆): δ 1.70-2.10 (m, 6H),2.29 (bs, 1H), 2.59 (m, 2H), 3.10-3.50 (m, 7H), 3.82 (m, 1H), 4.32-4.54(m, 4H), 5.01 (m, 1H), 6.29-6.41 (m, 4H), 7.20-7.35 (m, 5H), 7.57-7.61(m, 2H); MS [M-CF₃COO]⁺: 449.

EXAMPLE 182 Benzylphenylcarbamic acid 1-azabicyclo[2.2.2]oct-4-yl ester

The title compound was synthesised according to method a. The yield ofthe final step was 2.56 mg, 1%, as formate; ¹H-NMR (DMSO-d₆): δ 1.81 (m,6H), 2.83 (m, 6H), 4.81 (s, 2H), 7.14-7.32 (m, 10H), 8.24. (s, 1H); MS[M-HCOO]⁺: 337

The following examples illustrate pharmaceutical compositions accordingto the present invention and procedures for their preparation.

EXAMPLE 183 Preparation of a Pharmaceutical Composition: Tablets

Formulation: Compound of the present invention 5.0 mg Lactose 113.6 mgMicrocrystalline cellulose 28.4 mg Light silicic anhydride 1.5 mgMagnesium stearate 1.5 mg

Using a mixer machine, 15 g of the compound of the present invention wasmixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose.The mixture was subjected to compression moulding using a rollercompactor to give a flake-like compressed material. The flake-likecompressed material was pulverized using a hammer mill, and thepulverized material was screened through a 20 mesh screen. A 4.5 gportion of light silicic anhydride and 4.5 g of magnesium stearate wereadded to the screened material and mixed. The mixer product wassubjected to a tablets making machine equipped with a die/punch systemof 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150mg in weight

EXAMPLE 184 Preparation of a Pharmaceutical Composition: Tablets Coated

Formulation: Compound of the present invention 5.0 mg Lactose 95.2 mgCorn starch 40.8 mg Polyvinylpyrrolidone 7.5 mg Magnesium stearate 1.5mg Hydroxypropylcellulose 2.3 mg Polyethylene glycol 0.4 mg Titaniumdioxide 1.1 mg Purified talc 0.7 mg

Using a fluidized bed granulating machine, 15 g of the compound of thepresent invention was mixed with 285.6 g of lactose and 122.4 g of cornstarch. Separately, 22.5 g of polyvinylpyrrolidone was dissolved in127.5 g of water to prepare a binding solution. Using a fluidized bedgranulating machine, the binding solution was sprayed on the abovemixture to give granulates. A 4.5 g portion of magnesium stearate wasadded to the obtained granulates and mixed. The obtained mixture wassubjected to a tablet making machine equipped with a die/punch biconcavesystem of 6.5 mm in diameter, thereby obtaining 3,000 tablets, eachhaving 150 mg in weight Separately, a coating solution was prepared bysuspending 6.9 g of hydroxypropylmethylcellulose 2910, 1.2 g ofpolyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g ofpurified talc in 72.6 g of water. Using a High Coated, the 3,000 tabletsprepared above were coated with the coating solution to give film-coatedtablets, each having 154.5 mg in weight.

EXAMPLE 185 Preparation of a Pharmaceutical Composition: Liquid Inhalant

Formulation: Compound of the present invention 400 μg Physiologicalsaline 1 ml

A 40 mg portion of the compound of the present invention was dissolvedin 90 ml of physiological saline, and the solution was adjusted to atotal volume of 100 ml with the same saline solution, dispensed in 1 mlportions into 1 ml capacity ampoule and then sterilized at 115° for 30minutes to give liquid inhalant.

EXAMPLE 186 Preparation of a Pharmaceutical Composition: Powder Inhalant

Formulation: Compound of the present invention 200 μg Lactose 4,000 μg

A 20 g portion of the compound of the present invention was uniformlymixed with 400 g of lactose, and a 200 mg portion of the mixture waspacked in a powder inhaler for exclusive use to produce a powderinhalant.

EXAMPLE 187 Preparation of a Pharmaceutical Composition: InhalationAerosol

Formulation: Compound of the present invention 200 μg Dehydrated(Absolute) ethyl alcohol USP 8,400 μg 1,1,1,2-Tetrafluoroethane(HFC-134A) 46,810 μg

The active ingredient concentrate is prepared by dissolving 0.0480 g ofthe compound of the present invention in 2.0160 g of ethyl alcohol. Theconcentrate is added to an appropriate filling apparatus. The activeingredient concentrate is dispensed into aerosol container, theheadspace of the container is purged with Nitrogen or HFC-134A vapour(purging ingredients should not contain more than 1 ppm oxygen) and issealed with valve. 11.2344 g of HFC-134A propellant is then pressurefilled into the sealed container.

1-35. (canceled)
 36. A compound of formula (I):

wherein R1 represents a group chosen from phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl,thiophen-2-ylmethyl, and thiophen-3-ylmethyl; R2 represents a groupchosen from optionally substituted lower alkyl, optionally substitutedlower alkenyl, optionally substituted lower alkynyl, saturated orunsaturated cycloalkyl, saturated or unsaturated cycloalkylmethyl,phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl,thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, and pyridylmethyl;wherein the carbocyclic moieties in the cycloalkyl, cycloalkylmethyl,phenyl, benzyl or phenethyl groups are optionally bridged or fused toanother saturated, unsaturated or aromatic carbocyclic moiety or to acyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms; whereinthe cyclic groups present in R1 and R2 are optionally substituted byone, two or three, which may be identical or different, substituentschosen from halogen; straight or branched, optionally substituted loweralkyl; hydroxy; straight or branched, optionally substituted loweralkoxy; —SH; straight or branched optionally substituted loweralkylthio; nitro; cyano; —NR′R″; —CO₂R′; —C(O)—NR′R″; —N(R′″)C(O)—R′;and —N(R′″)—C(O)NR′R″; wherein R′, R″ and R′″, which may be identical ordifferent, are each independently chosen from a hydrogen atom, and astraight or branched, optionally substituted lower alkyl group, or R′and R″ together with the atom to which they are attached form a cyclicgroup; and p is 1 or 2 and the carbamate group is attached at positions2, 3 or 4 of the azabicyclic ring; or a pharmaceutically acceptable saltthereof or a stereoisomer thereof with the proviso that the compound offormula (I) is not one of Diphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester or Ethylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester.
 37. The compound of claim 36, whereinthe pharmaceutically acceptable salt is a quaternary ammonium salt offormula (II):

wherein R1 represents a group chosen from phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl,thiophen-2-ylmethyl, and thiophen-3-ylmethyl; R2 represents a groupchosen from optionally substituted lower alkyl, optionally substitutedlower alkenyl, optionally substituted lower alkynyl, saturated orunsaturated cycloalkyl, saturated or unsaturated cycloalkylmethyl,phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl,thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, and pyridylmethyl;wherein the carbocyclic moieties in the cycloalkyl, cycloalkylmethyl,phenyl, benzyl or phenethyl groups are optionally bridged or fused toanother saturated, unsaturated or aromatic carbocyclic moiety or to acyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms; whereinthe cyclic groups present in R1 and R2 are optionally substituted byone, two or three, which may be identical or different, substituentschosen from halogen; straight or branched, optionally substituted loweralkyl; hydroxy; straight or branched, optionally substituted loweralkoxy; —SH; straight or branched optionally substituted loweralkylthio; nitro; cyano; —NR′R″, —CO₂R′, —C(O)—NR′R″, —N(R′″)C(O)—R′,and —N(R′″)—C(O)NR′R″ groups, wherein R′, R″ and R′″, which may beidentical or different, are each independently chosen from a hydrogenatom and a straight or branched, optionally substituted lower alkylgroup, or R′ and R″ together with the atom to which they are attachedform a cyclic group; m is an integer ranging from 0 to 8; n is aninteger ranging from 0 to 4; A represents a group chosen from —CH₂—;—CH═CR′—; —CR′═CH—; —CR′R″—; —C(O)—, —O—, —S—, —S(O)—, —S(O)₂— and—NR′—, wherein R′ and R″, which may be identical or different, are eachindependently chosen from a hydrogen atom and a straight or branched,optionally substituted lower alkyl group, or R′ and R″ together with theatom to which they are attached form a cyclic group; B represents ahydrogen atom, or a group chosen from straight or branched, optionallysubstituted lower alkyl; hydroxy; straight or branched, optionallysubstituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR′; —OC(O)R′;—SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl;naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl;heteroaryl; and heterocyclyl; wherein R′ and R″, which may be identicalor different, are each independently chosen from a hydrogen atom and astraight or branched, optionally substituted lower alkyl group, or R′and R″ together with the atom to which they are attached form a cyclicgroup; and wherein the cyclic groups represented by B are optionallysubstituted by one, two or three, identical or different, substituentschosen from halogen; hydroxy; straight or branched, optionallysubstituted lower alkyl; phenyl; —OR′; —SR′; —NR′R″; —NHCOR′; —CONR′R″;—CN; —NO₂; and —COOR′; wherein R′ and R″ are each independently chosenfrom a hydrogen atom, or a straight or branched, optionally substitutedlower alkyl group, or R′ and R″ together with the atom to which they areattached form a cyclic group; and X⁻ represents a pharmaceuticallyacceptable anion of a mono or polyvalent acid; or stereoisomers thereof;or mixtures of stereoisomers thereof and stereoisomers of formula (I).38. The compound of claim 36, wherein when the cyclic group present inR1 is unsubstituted or has only one substitutent, R2 has at least onesubstituent.
 39. The compound of claim 36 wherein when R2 is notsubstituted, the cyclic group present in R1 has at least twosubstituents.
 40. The compound of claim 36, wherein when p is 2; thecarbamate group is attached at position 3 of the azabicyclic ring; andR1 is an unsubstituted indanyl group or a phenyl group, which isoptionally substituted with one or two, identical or different,substitutents chosen from chlorine, fluorine, bromine, methyl, hydroxyand cyano; then R2 cannot be one of: unsubstituted cyclopropylmethyl;unsubstituted cyclobutylmethyl; unsubstituted cyclopentylmethyl;cyclohexylmethyl optionally substituted with a methyl or an isopropenylgroup; unsubstituted cyclohexenyl; unsubstituted norbornenyl;unsubstituted bicycle[2,2,1]heptanyl; unsubstituted benzo[1;3]dioxolyl;unsubstituted 2,3-dihydrobenzo[1,4]dioxinyl; unsubstituted benzyl; abenzyl group which is substituted with one or two, identical ordifferent, substituents chosen from fluorine, chlorine, bromine,methoxy, methyl, trifluoromethyl, ethyl, tertbutyl, hydroxy,hydroxymethyl, cyano, aminocarbonyl, trifluoromethoxy, benzyloxy, andisopropyloxy; or a benzyl group which is substituted with three fluorineatoms.
 41. The compound of claim 36, wherein R1 represents a groupchosen from 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl,furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl; andthiophen-3-ylmethyl; wherein the cyclic group present in R1 isoptionally substituted by one, two, or three, identical or different,substituents chosen from halogen; straight or branched, optionallysubstituted lower alkyl; hydroxy; straight or branched, optionallysubstituted lower alkoxy; —SH; straight or branched optionallysubstituted lower alkylthio; nitro; cyano; —NR′R″; —CO₂R′; —C(O)—NR′R″;—N(R′″)C(O)—R′; and —N(R′″)—C(O)NR′R″; wherein R′, R″ and R′″ eachindependently represents a hydrogen atom or a straight or branched,optionally substituted lower alkyl group or R′ and R″ together with theatom to which they are attached form a cyclic group.
 42. The compound ofclaim 36, wherein R2 represents an optionally substituted group chosenfrom lower alkyl, lower alkenyl, lower alkynyl, saturated or unsaturatedcycloalkyl, phenyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl,thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, pyridylmethyl, and asaturated or unsaturated cycloalkylmethyl which has at least onesubstituent and is chosen from substituted cyclopropylmethyl,substituted cyclobutylmethyl and substituted cyclopentylmethyl; whereinthe substituents of the cyclic group present in R2 are one, two orthree, identical or different, substituents chosen from halogen;straight or branched, optionally substituted lower alkyl; hydroxy;straight or branched, optionally substituted lower alkoxy; —SH; straightor branched optionally substituted lower alkylthio; nitro; cyano;—NR′R″; —CO₂R′; —C(O)—NR′R″; —N(R′″)C(O)—R′; and —N(R′″)—C(O)NR′R″;wherein R′, R″ and R′″ each independently represents a hydrogen atom ora straight or branched, optionally substituted lower alkyl group or R′and R″ together with the atom to which they are attached form a cyclicgroup.
 43. The compound of claim 37, wherein when p is 2; the carbamategroup is attached at position 3 of the azoniabicyclic ring having(3R)-configuration; R1 is a phenyl group which is optionally substitutedwith a fluorine atom or a methyl group; R2 is an unsubstitutedcyclohexylmethyl group or a benzyl group which is optionally substitutedwith one or three fluorine atoms; and X⁻ is iodine; then, the sequenceB—(CH₂)_(n)-A-(CH₂)_(m)— cannot be a methyl group.
 44. The compound ofclaim 37, wherein the compound is not one of:(3R)-3-(Benzylphenylcarbamoyloxy)-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide;(3R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide;(3R)-3-(Benzyl-o-tolylcarbamoyloxy)-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide(3R)-1-Methyl-3-[o-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octaneiodide;(3R)-3-[(4-Fluorobenzyl)-m-tolylcarbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide;(3R)-3-[Benzyl-(2-fluorophenyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide; or(3R)-3-[Cyclohexylmethyl-(2-fluorophenyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octaneiodide.
 45. The compound of claim 37, wherein R1 represents a groupchosen from phenyl, 2-thienyl, 3-thienyl, thiophen-2-ylmethyl,thiophen-3-ylmethyl, furan-2-ylmethyl, and furan-3-ylmethyl, wherein thecyclic group present in R1 is optionally substituted with one, two, orthree, identical or different, substituents chosen from fluorine,chlorine, bromine, methyl, methoxy, trifluoromethyl, ethyl, tert-butyl,hydroxy, and cyano.
 46. The compound of claim 45, wherein R1 representsa group chosen from phenyl, 2-fluorophenyl, 3-flurorophenyl,4-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2,4,5-trifluorophenyl, 5-methylfuran-2-ylmethyl,4-fluoro-2-methylphenyl, 3-fluoro-4-methoxyphenyl,3-methyl-thiophen-2-ylmethyl, 4,5-dimethyl-thiophen-2-ylmethyl,thiophen-3-ylmethyl, 5-methyl-furan-2-ylmethyl,5-methyl-2-trifluoromethyl-furan-3-ylmethyl, and2,5-dimethyl-furan-3-ylmethyl.
 47. The compound of claim 37, wherein R2represents a group chosen from pent-4-enyl, pentyl, butyl, allyl,benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl,furan-3-ylmethyl, phenethyl, cyclopentyl, cyclohexyl, andcyclohexylmethyl, wherein the cyclic group present in R2 is optionallysubstituted with one, two, or three, identical or different,substituents chosen from fluorine, chlorine, bromine, methyl, methoxy,trifluoromethyl, ethyl, tert-butyl, hydroxy, and cyano.
 48. The compoundof claim 47, wherein R2 represents a group chosen from 3-fluorobenzyl,2,4,5-trifluorobenzyl, 3,4,5-trifluorobenzyl,5-bromothiophen-2-ylmethyl, 3,4-dimethoxyphenylethyl,3-methylthiophen-2-ylmethyl, thiophen-3-ylmethyl,4-bromo-5-methylthiophen-2-ylmethyl, 4,5-dimethylfuran-2-ylmethyl,furan-3-ylmethyl, 2-fluoro-4-methoxybenzyl, 2-(4-fluorophenyl)ethyl,butyl, pent-4-enyl, and cyclopentyl.
 49. The compound of claim 37,wherein A is —CH₂—; m and n are both 0; B represents a group chosen fromstraight or branched, optionally substituted lower alkyl; hydroxy;straight or branched, optionally substituted lower alkoxy; cyano; nitro;—CH═CR′R″; —C(O)OR′; —OC(O)R; —SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″;—NR′C(O)NR″; cycloalkyl; phenyl; naphthanelyl;5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl; heteroaryl; andheterocyclyl; and R′ and R″ are each independently chosen from ahydrogen atom and a straight or branched, optionally substituted loweralkyl group, or R′ and R″ together with the atom to which they areattached form a cyclic group; and wherein the cyclic groups representedby B are optionally substituted by one, two or three, identical ordifferent, substituents chosen from halogen; hydroxyl; straight orbranched, optionally substituted lower alkyl; phenyl; —OR′; —SR′;—NR′R″; —NHCOR′; —CONR′R″; —CN, —NO₂ and —COOR′; wherein R′ and R″ areeach independently chosen from a hydrogen atom, or a straight orbranched, optionally substituted lower alkyl group, or R′ and R″together with the atom to which they are attached form a cyclic group.50. The compound of claim 37, wherein A is —CH₂—; B represents ahydrogen atom, or a group chosen from straight or branched, optionallysubstituted lower alkyl; hydroxy; straight or branched, optionallysubstituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR′; —OC(O)R′;—SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl;naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl;heteroaryl; and heterocyclyl; wherein R′ and R″ are each independentlychosen from a hydrogen atom and a straight or branched, optionallysubstituted lower alkyl group, or R′ and R″ together with the atom towhich they are attached form a cyclic group; and wherein the cyclicgroup represented by B is optionally substituted by one, two or three,identical or different, substituents chosen from halogen; hydroxy;straight or branched, optionally substituted lower alkyl; phenyl; —OR′;—SR′; —NR′R″; —NHCOR′; —CONR′R″; —CN; —NO₂; and —COOR′; wherein R′ andR″ are each independently chosen from a hydrogen atom, or a straight orbranched, optionally substituted lower alkyl group, or R′ and R″together with the atom to which they are attached form a cyclic group;and at least one of m or n is not
 0. 51. The compound of claim 37,wherein B represents a thiophen-2-yl group or a phenyl group which isoptionally substituted with one, two, or three, identical or different,substituents chosen from halogen atoms and hydroxy, methyl, —CH₂OH,—OMe, —NMe₂, —NHCOMe, —CONH₂, —CN, —NO₂, —COOMe, and —CF₃ groups. 52.The compound of claim 51, wherein B represents a group chosen fromphenyl, 4-fluorophenyl, 3-hydroxyphenyl, and thiophen-2-yl.
 53. Thecompound of claim 37, wherein n=0 or 1; m is an integer ranging from 1to 6; and A represents a group chosen from —CH₂—, —CH═CH—, —CO—, —NMe-,—O—, and —S—.
 54. The compound of claim 53, wherein m is an integerequal to 1, 2 or 3 and A represents a group chosen from —CH₂—, —CH═CH—,and —O—.
 55. The compound of claim 37, wherein B—(CH₂)_(n)-A-(CH₂)_(m)—represents a group chosen from 3-phenoxypropyl, 2-phenoxyethyl,3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl,3-(4-fluorophenoxy)propyl, 3-thiophen-2-ylpropyl, allyl, heptyl,3-cyanopropyl, and methyl.
 56. The compound of claim 37, wherein X⁻represents anion chosen from chloride, bromide, trifluoroacetate, andmethanesulphonate.
 57. The compound of claim 36, wherein p is
 2. 58. Thecompound of claim 36, wherein the azabicyclic ring is substituted in the3-position.
 59. The compound of claim 58, wherein the carbon at the3-position of the azabicyclic ring has R configuration.
 60. The compoundof claim 58, wherein the carbon at the 3-position of the azabicyclicring has S configuration.
 61. The compound of claim 36, wherein thecompound of formula (I) is a single isomer.
 62. The compound of claim36, chosen from:[2-(3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(5-Bromothiophen-2-ylmethyl)-(2,4,5-trifluorophenyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl esterThiophen-3-ylmethyl-(2,4,5-trifluorobenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(4-Bromo-5-methylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamicacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;Furan-3-ylmethyl-(5-methyl-2-trifluoromethylfuran-3-ylmethyl)carbamicacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester;(2,5-Dimethylfuran-3-ylmethyl)-(2-fluoro-4-methoxybenzyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;[2-(4-Fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester;Butyl-(2,5-difluorophenyl)carbamic acid (3R)-1-azabicyclo[2.2.2]oct-3-ylester; (2,6-Difluorophenyl)pent-4-enylcarbamic acid(3R)-1-aza-bicyclo[2.2.2]oct-3-yl ester;Cyclopentyl-(4,5-dimethylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester; and(5-Ethylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester.
 63. The compound of claim 36,chosen from:(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide;(3R)-3-[(3-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide;(3R)-1-(2-Phenoxyethyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide;(3R)-1-(3-Phenylpropyl)-3-[m-tolyl-(2,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide;(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide;(3R)-1-Allyl-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide;(3R)-3-[(5-Bromothiophen-2-ylmethyl)-(2,4,5-trifluorophenyl)carbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-1-Phenethyl-3-[thiophen-3-ylmethyl-(2,4,5-trifluorobenzyl)carbamoyloxy-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[(4-Bromo-5-methylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[(4,5-Dimethylfuran-2-ylmethyl)-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-1-[3-(4-Fluorophenoxy)propyl]-3-[furan-3-ylmethyl-(5-methyl-2-trifluoromethylfuran-3-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[(2,5-Dimethylfuran-3-ylmethyl)-(2-fluoro-4-methoxybenzyl)carbamoyloxy]-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-1-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[Butyl-(2,5-difluorophenyl)carbamoyloxy]-1-heptyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-1-(3-cyanopropyl)-3-[(2,6-difluorophenyl)pent-4-enylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate;(3R)-3-[Cyclopentyl-(4,5-dimethylthiophen-2-ylmethyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2}octanetrifluoroacetate;(3R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide;(3R)-3-[(5-Ethylthiophen-2-ylmethyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide;(3R)-3-[[2-(3,4-dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamoyloxy]-1-(4-ethoxycarbonylbutyl)-1-azoniabicyclo[2.2.2]octaneformate;(3R)-3-[(4-Fluoro-2-methylphenyl)-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide;(3R)-3-[(3-Fluoro-4-methoxyphenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanebromide; and(3R)-1-Allyl-3-[2-(4-fluorophenyl)ethyl]-(3-methylthiophen-2-ylmethyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octanebromide.
 64. A pharmaceutical composition comprising at least onecompound of claim 36, and at least one pharmaceutically acceptablecarrier or diluent.
 65. The compound of claim 36, wherein the compoundis effective for the treatment of a pathological condition or diseasesusceptible to amelioration by antagonism of M3 muscarinic receptors.66. A method for treating a subject afflicted with a pathologicalcondition or disease susceptible to amelioration by antagonism of M3muscarinic receptors, comprising administering to said subject aneffective amount of at least one compound of claim
 36. 67. The methodaccording to claim 66, wherein the pathological condition is chosen fromrespiratory, urological, and gastrointestinal disease or disorder.
 68. Acombination product comprising, (i) at least one first compound of claim36; and (ii) at least one second compound effective in the treatment ofat least one pathological condition chosen from respiratory, urological,and gastrointestinal disease or disorder, wherein the at least one firstcompound and the at least one second compound are administeredsimultaneously, separately, or sequentially.
 69. A combination productcomprising, (i) at least one first compound of claim 36; and (ii) atleast one second compound chosen from a β₂ agonist, steroid,antiallergic drug, phosphodiesterase IV inhibitor, and a leukotriene D4(LTD4) antagonist, wherein the at least one first compound and the atleast one second compound are administered simultaneously, separately,or sequentially in the treatment of a respiratory disease.